CN101400679A - Spiroindolinone derivatives - Google Patents

Spiroindolinone derivatives Download PDF

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CN101400679A
CN101400679A CNA2007800085648A CN200780008564A CN101400679A CN 101400679 A CN101400679 A CN 101400679A CN A2007800085648 A CNA2007800085648 A CN A2007800085648A CN 200780008564 A CN200780008564 A CN 200780008564A CN 101400679 A CN101400679 A CN 101400679A
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chloro
phenyl
replacement
indoles
racemize
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CN101400679B (en
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丁清杰
刘进军
张筑明
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Priority claimed from PCT/EP2007/052220 external-priority patent/WO2007104714A1/en
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Abstract

The present invention relates to spiroindolinone derivatives of the formula (I) and enantiomers and pharmaceutically acceptable salts and esters thereof which have utility as antiproliferative agents, especially, as anticancer agents.

Description

Spiroindolinone derivatives
The present invention relates to the Spiroindolinone derivatives of following formula I, formula II or formula III,
Figure A200780008564D00151
Or
Figure A200780008564D00152
And enantiomer and pharmaceutical salts and ester,
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 9 ', R 10As described herein.
Described compound has as antiproliferative, particularly as the effect of carcinostatic agent.
P53 is the tumor suppressor protein that plays a crucial role in preventing the cancer generation.Its protection cell integrity and the propagation of preventing the clone of cell permanent lesion by induced growth inhibition or apoptosis.On molecular level, p53 can activate one group to relate to the gene transcription factor of regulating cell cycle and apoptosis.P53 is the effective cell cycle inhibitor that closely regulated by MDM2.MDM2 and p53 form feedback control loop.MDM2 can and suppress the ability of its trans-activation p53-regulatory gene in conjunction with p53.In addition, the MDM2 mediation relies on the p53 degraded of ubiquitin.P53 can activate MDM2 genetic expression, increases the proteic cell levels of MDM2 thus.This feedback control loop guaranteed MDM2 and p53 in normal proliferative cell, all remain on low-level on.MDM2 also is the cofactor of E2F, and it plays a crucial role in Cycle Regulation.
The ratio of MDM2 and p53 (E2F) is subjected to unusual adjusting in many cancers.For example, confirmed to take place usually on the p16INK4/p19ARF locus the damaged MDM2 proteolytic degradation that influenced of molecule.Suppressing MDM2-p53 should cause p53 accumulation, cell cycle to be suppressed and/or apoptosis with the interaction of wild type p53 in tumour cell.Therefore, the MDM2 antagonist as unitary agent can for cancer therapy provide new tool or with other antitumor therapy coupling of wide spectrum.Be used to suppress the feasibility that the interactional different macromole instruments of MDM2-p53 (for example antibody, antisense oligonucleotide, peptide class) have confirmed this strategy by use.MDM2 also by as the conservative land of the p53 E2F-dependent transcription in conjunction with E2F and activating cells cyclin A, points out the MDM2 antagonist to have effect in the p53 mutant cells thus.
At J.Am Chem.Soc., a series of Spiroindolinones as the MDM2 antagonist are disclosed in 2005,127,10130 in advance.
The invention provides Spiroindolinone derivatives, they are the interactional micromolecular inhibitors of MDM2-p53.In acellular and test based on cell, compound exhibits of the present invention goes out to suppress the interaction of MDM2 albumen and p53-sample peptide.In the test based on cell, these compounds have proved machine-processed activity (mechanistic activity).Cancer cells is incubated with wild type p53 causes p53 albumen accumulation, induce p21 gene that p53-regulates and cell cycle arrest, caused at external effective antiproliferative activity to the wild type p53 cell in G1 and G2 phase.On the contrary, under suitable compound concentration, in the cancer cells that has mutant p53, do not observe these activity.Therefore, the activity of MDM2 antagonist is relevant with its mechanism of action probably.These compounds can be carcinostatic agents effectively and optionally.
The present invention relates to 3 of following formula I, formula II or formula III, 3 '-Spiroindolinone,
Figure A200780008564D00161
Or
Figure A200780008564D00171
Wherein
X is selected from hydrogen, halogen, and cyano group, nitro, ethynyl, cyclopropyl, methyl, ethyl, sec.-propyl, methoxyl group, and vinyl,
Y is hydrogen or fluorine,
R 4, R 5Be selected from hydrogen and low alkyl group,
R 1And R 8In one be selected from low alkyl group,
The low alkyl group that replaces, low-grade alkenyl, the low-grade alkenyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle of replacement, cycloalkyl, the cycloalkyl of replacement, cycloalkenyl group and the cycloalkenyl group that replaces, and another is hydrogen,
R 6And R 7In one be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl that replaces, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle that replaces, cycloalkyl, the cycloalkyl of replacement, cycloalkenyl group and the cycloalkenyl group that replaces, and another is a hydrogen, low alkyl group or cyano group
R 2Be selected from hydrogen, low alkyl group, replacement
Low alkyl group, C (=O) R 9, C (=O) NHR 9, C (=O) NR 9R 9 'And C (=O) OR 9,
R 3Be selected from NHR 9, SR 9, and NR 9R 9 ',
R 9Be selected from low alkyl group, the low alkyl group of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle of replacement, the cycloalkyl of cycloalkyl and replacement,
R 9Be selected from the low alkyl group of low alkyl group and replacement,
And at R 9And R 9Situation under, they can connect independently with formation and are selected from ring texture in the heterocycle of heterocycle or replacement,
R 10Be selected from hydrogen, hydroxyl and low alkyl group,
And pharmaceutical salts and ester.
Preferably have formula I compound suc as formula the stereochemical structure shown in the IV,
Figure A200780008564D00181
Wherein
X is Cl or Br,
Y is a hydrogen,
R 1Be hydrogen,
R 4And R 5All be hydrogen,
R 6Be hydrogen,
R 7Be the phenyl of replacement or the heteroaryl of replacement, the phenyl of wherein said replacement or the heteroaryl of replacement are selected from:
Figure A200780008564D00182
R 8Be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, cycloalkyl, the cycloalkyl of replacement, the cycloalkenyl group of cycloalkenyl group and replacement,
R 3Be selected from NHR 9And NR 9R 9 ',
R 9Be selected from low alkyl group, the low alkyl group of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle of replacement, the cycloalkyl of cycloalkyl and replacement,
R 9 'Be selected from the low alkyl group of low alkyl group and replacement,
And at R 9And R 9 'Situation under, they can connect independently with formation and are selected from ring texture in the heterocycle of heterocycle or replacement,
And pharmaceutical salts and ester.
Further preferably have formula II compound suc as formula the stereochemical structure shown in the V,
Figure A200780008564D00191
Wherein
X is Cl or Br,
Y is a hydrogen,
R 1Be hydrogen,
R 4And R 5All be hydrogen,
R 6Be hydrogen,
R 7Be the phenyl of replacement or the heteroaryl of replacement, the phenyl of wherein said replacement or the heteroaryl of replacement are selected from:
Figure A200780008564D00192
R 8Be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, cycloalkyl, the cycloalkyl of replacement, the cycloalkenyl group of cycloalkenyl group and replacement,
R 10Be hydrogen, hydroxyl, and methyl,
And pharmaceutical salts and ester.
Further preferably have formula III compound suc as formula the stereochemical structure shown in the VI,
Figure A200780008564D00201
Wherein
X is Cl or Br,
Y is a hydrogen,
R 1Be hydrogen,
R 4And R 5All be hydrogen,
R 6Be hydrogen,
R 7Be the phenyl of replacement or the heteroaryl of replacement, the phenyl of wherein said replacement or the heteroaryl of replacement are selected from:
Figure A200780008564D00202
R 8Be selected from low alkyl group, the alkyl of replacement, low-grade alkenyl, the low-grade alkenyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, cycloalkyl, the cycloalkyl of replacement, the cycloalkenyl group of cycloalkenyl group and replacement,
R 2Be selected from hydrogen, low alkyl group, replacement
Low alkyl group, C (=O) R 9, C (=O) NHR 9, C (=O) NR 9R 9 'And C (=O) OR 9,
R 9Be selected from low alkyl group, the low alkyl group of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the cycloalkyl of cycloalkyl and replacement,
R 9 'Be selected from the low alkyl group of low alkyl group and replacement,
And at R 9And R 9 'Situation under, they can connect independently with formation and are selected from ring texture in the heterocycle of heterocycle and replacement,
And pharmaceutical salts and ester.
Other preferably has the formula III compound suc as formula the stereochemical structure shown in the VII,
Figure A200780008564D00211
Wherein
X is Cl or Br,
Y is a hydrogen,
R 1Be hydrogen,
R 4And R 5All be hydrogen,
R 6Be hydrogen,
R 8Be the phenyl that replaces, the phenyl of wherein said replacement is selected from:
Figure A200780008564D00212
R 7Be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle of replacement, cycloalkyl, the cycloalkyl of replacement, the cycloalkenyl group of cycloalkenyl group and replacement,
R 2Be selected from hydrogen, low alkyl group, replacement
Low alkyl group, C (=O) R 9, C (=O) NHR 9, C (=O) NR 9R 9 'And C (=O) OR 9,
R 9Be selected from low alkyl group, the low alkyl group of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the cycloalkyl of cycloalkyl and replacement,
R 9 'Be selected from the low alkyl group of low alkyl group and replacement,
And at R 9And R 9 'Situation under, they can connect independently with formation and are selected from ring texture in the heterocycle of heterocycle and replacement,
And pharmaceutical salts and ester.
Those compounds that particularly preferred compound is a following formula:
Racemize (2 ' S, 3S, 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(2, the 2-dimethyl propyl) spiral shells [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' S, 3R)-6-chloro-2 '-(3-chloro-phenyl-)-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-4 '-sec.-propyl-6 '-(methylthio group) spiral shell [3H-indoles-3,3 '-pyridine]-2 (1H)-ketone,
Racemize (2 ' S, 3S, 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-ethyl spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S, 5 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-cyano-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 3-3,5-dimethylphenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(trifluoromethyl)-phenyl)] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' S, 3R)-6-chloro-4 '-(3-chloro-phenyl-)-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-6 '-(methylthio group)-2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-pyridine]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,4 difluorobenzene base) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-naphthyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-pyridyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3,4-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(3, the 4-difluorophenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone,
Racemize (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(5-fluoro-2-aminomethyl phenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-aminomethyl phenyls) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(the 1-ethyl-
Propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(2,5-dimethyl-phenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl-2H-pyrazole-3-yl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-(morpholine-4-carbonyl)-2 '-(1-naphthyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(4-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' S, 3S, 4 ' R)-1 '-tertiary butyl aminocarboxyl-6-chloro-4 '-(4-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(4-chloro-phenyl)-1 '-(3-cyano group-phenyl amino carbonyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-1 '-(3-cyano group-phenyl amino carbonyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-tertiary butyl aminocarboxyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-benzoyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-ethanoyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-[4-(amino carbonyl methyl)-piperazine-1-carbonyl]-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl)-1 '-[4-(3-methylsulfonyl-propyl group)-piperazine-1-carbonyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl)-1 '-[4-(2-oxo-2-tetramethyleneimine-1-base-ethyl)-piperazine-1-carbonyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-[4-(2-acetylamino-ethyl)-piperazine-1-carbonyl]-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl)-1 '-[4-(2-hydroxyl-ethyl)-piperazine-1-carbonyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-1 '-cyclohexyl aminocarboxyl-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-benzylamino carbonyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(2,3-two fluoro-6-isopropoxy-phenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone,
Chirality (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(2,3-two fluoro-6-isopropoxy-phenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-hydroxycarbonyl group methyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(1-methylene radical-butyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone,
Chirality (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(1-methylene radical-butyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone,
Racemize (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-3 '-methyl-5 '-(1-methylene radical-butyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone, racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-(1, the 4-piperazinyl)-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-[4-[1,1-dimethyl oxyethyl group-carbonyl] amino] ethylamino-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-[4-amino] ethylamino-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone, trifluoroacetic acid,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-(4-methyl isophthalic acid-piperazinyl)-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-[[tetrahydrochysene-1,1-dioxo-2H-thiapyran-4-yl] piperazinyl-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone
Racemize (2 ' R; 3 ' R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-[4-(3-methyl sulphonyl)-propyl group] piperazinyl-spiral shell [3H-indoles-3; 3 '-2 '; 3 '; 4 '; 5 '-tetrahydrochysene-pyridine]-2-ketone; and racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-[1-methyl sulphonyl-4-piperidyl] amino-spiral shell [3H-indoles-3; 3 '-2 '; 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone.
In this manual, when indication, various groups can be by 1-5, or preferred 1-3 substituting group replaces, described substituting group is independently selected from: low alkyl group, and rudimentary-thiazolinyl, rudimentary-alkynyl, dioxo-rudimentary-alkylidene group (forms for example phendioxin, the 3-dioxa cyclopentenyl), halogen, hydroxyl, CN, CF 3, NH 2, N (H, rudimentary-alkyl), N (rudimentary-alkyl) 2, aminocarboxyl, carboxyl, NO 2, rudimentary-alkoxyl group, sulfo--rudimentary-alkoxyl group; rudimentary-alkyl sulphonyl, amino-sulfonyl, rudimentary-alkyl-carbonyl; rudimentary-the alkyl-carbonyl oxygen base, rudimentary-alkoxy carbonyl, rudimentary-alkyl-carbonyl-NH; fluoro-is rudimentary-alkyl, and fluoro-is rudimentary-alkoxyl group, rudimentary-alkoxyl group-carbonyl-rudimentary-alkoxyl group; carboxyl-rudimentary-alkoxyl group; formamyl-rudimentary-alkoxyl group, hydroxyl-rudimentary-alkoxyl group, NH 2-rudimentary-alkoxyl group, N (H, rudimentary-alkyl)-rudimentary-alkoxyl group, N (rudimentary-alkyl) 2-rudimentary-alkoxyl group, benzyloxy-rudimentary-alkoxyl group, single-or amino-alkylsulfonyl of replacing of two-low alkyl group and can choose by halogen hydroxyl, NH wantonly 2, N (H, rudimentary-alkyl) or N (rudimentary-alkyl) 2Rudimentary-the alkyl that replaces.For aryl, heteroaryl and heterocyclic preferred substituents are halogens, lower alkoxy, low alkyl group and amino.
If alkyl, thiazolinyl, two ends of alkynyl or similar group are connected on the identical part, then can obtain ring texture, two hydrogen of wherein said part are by described alkyl, thiazolinyl, two terminal replacements of alkynyl or similar group, thus produce ring texture, as 1,2,3, the 4-tetraline, greatly the ring or spirocyclic compound in.
Term " alkyl " is meant to have the 1 straight or branched saturated hydrocarbyl to about 20 carbon atoms, comprises having 1 group to about 7 carbon atoms.In certain embodiments, alkyl substituent can be a low-grade alkyl substituent.Term " low alkyl group " is meant the alkyl with 1 to 6 carbon atom, and in certain embodiments, is the alkyl with 1 to 4 carbon atom.The example of alkyl includes but not limited to, methyl, and ethyl, just-and propyl group, different-propyl group, just-and butyl, the second month in a season-butyl, tert-butyl, just-amyl group, and the second month in a season-amyl group.
As used herein, " cycloalkyl " means any stable monocycle or the multi-loop system of only being made up of carbon atom, its any ring is saturated, and term " cycloalkenyl group " means any stable monocycle or the multi-loop system of only being made up of carbon atom, and its at least one ring is that part is unsaturated.The example of cycloalkyl includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, adamantyl, the ring octyl group, bicyclic alkyl comprises double-octane as [2.2.2] double-octane or [3.3.0] double-octane, and bicyclic nonane is as [4.3.0] bicyclic nonane, with the dicyclo decane as [4.4.0] dicyclo decane (naphthane), or spirocyclic compound.The example of cycloalkenyl group includes but not limited to, cyclopentenyl or cyclohexenyl.
Term " thiazolinyl " is meant and contains two keys and have 2 to 6, the unsaturation straight or branched aliphatic hydrocarbyl of preferred 2 to 4 carbon atoms as used herein.The example of like this " thiazolinyl " is a vinyl, allyl group, pseudoallyl, 1-propenyl, 2-methyl isophthalic acid-propenyl, 1-butylene base, crotyl, the 3-butenyl, 2-ethyl-1-butylene base, 3-methyl-2-butene base, the 1-pentenyl, pentenyl, 3-pentenyl, the 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.
Term " alkynyl " is meant and contains one three key and have 2 to 6, the unsaturation straight or branched aliphatic hydrocarbyl of preferred 2 to 4 carbon atoms as used herein.The example of like this " alkynyl " is an ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base and 5-hexin base.
Be meant fluorine as employed term " halogen " in definition, chlorine or bromine, preferred fluorine and chlorine.
" aryl " is meant the aromatic carbocyclic alkyl of univalent monocycle or dicyclo, the first aromatic ring of preferred 6-10 system.Preferred aryl groups includes but not limited to, phenyl, naphthyl, tolyl, and xylyl.
" heteroaryl ＂ is meant and contains the aromatic heterocycle system of two rings at the most.Preferred heteroaryl includes but not limited to thienyl, furyl, indyl, pyrryl, pyridyl, pyrazinyl ， oxazolyl, thiazolyl (thiaxolyl), quinolyl, pyrimidyl, imidazoles and tetrazyl.
Under the situation of the aryl of dicyclo or heteroaryl, should be understood that a ring can be an aryl, and another is a heteroaryl, and two all is to replace or unsubstituted.
" heterocycle " be meant and replace or unsubstituted 5 to 8 yuan of lists-or the aromatics or the non-aromatic hydrocarbon of dicyclo, and wherein the heteroatoms that is selected from nitrogen, oxygen or the sulphur atom of 1 to 3 carbon atom replaces.Example comprises tetramethyleneimine-2-base; Tetramethyleneimine-3-base; Piperidyl; Morpholine-4-base etc.
" heteroatoms " is meant and is selected from N, the atom among O and the S.
" alcoxyl, alkoxyl group or lower alkoxy " is meant any above-mentioned low alkyl group that is connected on the Sauerstoffatom.Typical lower alkoxy comprises: methoxyl group, oxyethyl group, isopropoxy or propoxy-, butoxy etc.What further comprise in the implication of alkoxyl group is a plurality of alkoxyl group side chains, ethoxy ethoxy for example, methoxy ethoxy, methoxy ethoxy oxyethyl group etc.; With the alkoxyl group side chain that replaces, dimethylamino ethoxy for example, diethyl amino base oxethyl, dimethoxy-phosphoryl methoxy base etc.
" medicinal " is meant for the experimenter who gives specific compound it is acceptable and essentially no toxic on the pharmacology as pharmaceutical carrier, vehicle etc.
" pharmaceutical salts " is meant the biological effectiveness that keeps The compounds of this invention and characteristic and the conventional acid additive salt or the base addition salt that are formed by suitable nontoxicity organic acid or mineral acid or organic bases or mineral alkali.The example of acid salt comprise salt that those derive from mineral acid, all example hydrochloric acids, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, thionamic acid, phosphoric acid and nitric acid and those derive from organic acid, such as the salt of tosic acid, Whitfield's ointment, methylsulfonic acid, oxalic acid, succsinic acid, citric acid, oxysuccinic acid, lactic acid, fumaric acid, trifluoroacetic acid etc.The example of base addition salt comprises that those derive from salt, for example tetramethylammonium hydroxide of ammonium, potassium, sodium and quaternary ammonium hydroxide.With medical compounds (being medicine) chemically modified salify is physics and chemical stability, water absorbability, flowability and the deliquescent technology that the well-known acquisition compound of pharmacist improves.For example, referring to " pharmaceutical dosage form and drug delivery systems " such as Ansel (PharmaceuticalDosage Forms and Drug Delivery Systems) (the 6th edition 1995) 196 and 1456-1457 page or leaf.
Formula I-VII compound and their salt have at least one unsymmetrical carbon, therefore can be used as racemic mixture or different steric isomer existence.Can separate various isomer by separation known method such as chromatography.
Compound of the present invention can be used for treatment or control cell proliferation disorders, particularly tumor disease.These compounds can be used for the treatment of or the controlled entity knurl with the preparation that contains these compounds, such as mammary gland, colon, lung and tumor of prostate.
Treatment significant quantity according to compound of the present invention is meant effective prevention, alleviation or improves disease symptoms or the consumption of the prolongation experimenter's survival time for the treatment of.The scope of determining to belong to art technology of treatment significant quantity.
The treatment significant quantity of The compounds of this invention or dosage can change in wide limit, and can measure according to mode well known in the art.Can comprise particular compound, route of administration, disease of being treated that is given and the patient who is treated according to the such dosage of individual need adjustment in every kind of particular case.In general, under the situation of or parenteral admin oral the grownup who body weight is about 70Kg, about 10mg is to about 10,000mg, and preferably about 200mg is extremely about 1, and dosage every day of 000mg should be suitable, but, when in case of necessity, can surpass the upper limit.Can with every day dosage with single dose or divided dose form administration, or for parenteral admin, can be with the continuous infusion form administration.
Preparation of the present invention comprises and is suitable for following those: oral, nose, part (comprising oral cavity and hypogloeeis), rectum, vagina and/or parenteral admin.Said preparation can exist with unit dosage form easily, and can be by method preparation known in the pharmacopedics field.Can will change according to the main body that will treat and the ad hoc fashion of administration with the amount of solid support material combination with the activeconstituents of generation single dose form.Can will be the amount that produces the formula I-VII compound of result of treatment usually with the amount of the activeconstituents that produces the single dose form with solid support material combination.Usually, in 100 per-cents, the scope of this amount is about 1% to about 99% activeconstituents, and preferred about 5% to about 70%, most preferably from about 10% to about 30%.
Preparing these preparations or method for compositions may further comprise the steps: with compound of the present invention and carrier, and one or more optional ancillary component combinations.Usually, by with compound of the present invention and liquid vehicle or solid carrier in small, broken bits, or they both, evenly and combination nearly, then, if desired, with formed product.
The preparation that the present invention is suitable for oral administration can be following form: capsule, cachet, sachet, pill, tablet, lozenge (use the matrix (flavored basis) of flavoring, normally sucrose and gum arabic or tragacanth gum), pulvis, granule or as solution or suspension agent in water-based or non-aqueous liquid, or as oil-in-water or water-in-oil liquid gelatin and glycerine, or sucrose and gum arabic) and/or mouth wash shua etc., the The compounds of this invention that contains predetermined amount separately is as activeconstituents.Can also be with compound of the present invention as bolus (bolus), electuary or paste administration.
" significant quantity " is meant effective prevention, alleviation or improves disease symptoms or the consumption of the prolongation experimenter's survival time for the treatment of.
" IC 50" be meant and suppress the concrete concentration of measuring active 50% needed specific compound.Wherein, IC 50Can measure as described later.
" medicinal ester " is meant the general formula I that has carboxyl or the hydroxyl-VII compound of conventional esterification, this ester class kept the biological effectiveness of general formula I-IV compound and characteristic and in vivo (in vivo) be cracked into corresponding active carboxylic acid or alcohol respectively.
Synthetic
The present invention relates to prepare method, the method for the compound of preferred following formula V or formula V ' according to compound of the present invention:
Figure A200780008564D00291
Or
Figure A200780008564D00292
Wherein
X is selected from hydrogen, halogen, cyano group, nitro, cyclopropyl, methyl, ethyl, and sec.-propyl;
Y is hydrogen or fluorine;
R 1Be hydrogen;
R 4And R 5Be hydrogen or low alkyl group;
R 8Be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle of replacement, cycloalkyl, the cycloalkyl of replacement, cycloalkenyl group and the cycloalkenyl group that replaces;
R 6And R 7In one be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl that replaces, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle that replaces, cycloalkyl, the cycloalkyl of replacement, cycloalkenyl group and the cycloalkenyl group that replaces, and another is a hydrogen, cyano group or low alkyl group
This method comprises: at about 110-160 ℃ and under anhydrous condition, make the compound of following formula,
With the compound reaction of following formula,
Compound with preparation formula V or V '.
The invention still further relates to the method for preparation, the method for the compound of preferred following formula V or formula V ' according to compound of the present invention:
Figure A200780008564D00303
Or
Figure A200780008564D00304
Wherein
X is selected from hydrogen, halogen, cyano group, nitro, cyclopropyl, methyl, ethyl, and sec.-propyl;
Y is hydrogen or fluorine;
R 1Be hydrogen;
R 4And R 5Be hydrogen or low alkyl group;
R 8Be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle of replacement, cycloalkyl, the cycloalkyl of replacement, cycloalkenyl group and the cycloalkenyl group that replaces;
R 6And R 7In one be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl that replaces, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle that replaces, cycloalkyl, the cycloalkyl of replacement, cycloalkenyl group and the cycloalkenyl group that replaces, and another is a hydrogen, cyano group or low alkyl group
This method comprises: the compound that makes following formula
Figure A200780008564D00311
With suitable blocking group (Pg) reaction, so that the compound of following formula to be provided,
Figure A200780008564D00312
Then,, make the compound reaction of itself and following formula at about 110-160 ℃ and under anhydrous condition,
Then with the product deprotection that obtains, with the compound of preparation formula V and V '.
The compounds of this invention among the formula I-VII can be synthetic according to following general scheme.For what those of ordinary skill in the art understood easily be, can be in general synthetic route by the replacement of reagent or reagent the compound among the preparation formula I-VII.Raw material is commercially available, or can be synthetic by the known literature method used for a long time of those of ordinary skill in the art.
Scheme 1
Figure A200780008564D00321
Usually, the suitable aldehyde I that selects can with hexamethl disilamine base lithium, the acyl chlorides that chlorine trialkyl silane and selectivity replace reacts in the multistep mode in single jar, generating 2-azepine-1,3-butadiene II (scheme I), and can be used as raw product.Ghosez, people such as L have reported preparation and their formation heterocyclic application (reference: Tetrahedron 1995,11021 in azepine Diels-Alder reaction of 2-azepine-1,3-butadiene; J.Am.Chem.Soc.1999,2617; The document of wherein quoting).The suitable aldehyde I that selects is commercially available, or can be synthetic by various kinds of document method used for a long time.
Figure A200780008564D00322
Racemic mixture
In the presence of alkali, under heating condition, at protonic solvent such as methyl alcohol, ethanol or aprotic solvent such as toluene, in the o-Xylol, oxindole III can react with the suitable aldehydes or ketones that replaces, to obtain intermediate compound IV.Normally used alkali is tetramethyleneimine or piperidines.Then in toluene or o-Xylol, under about 110 ℃ to 160 ℃ heating and anhydrous condition, intermediate compound IV can with the reaction of 2-azepine-1,3-butadiene II, provide show with other minority steric isomer together, as the Spiroindolinone V of primary product and the racemic mixture of V '.That 6-replaces or 5,6-disubstituted oxindoles III raw material is commercially available, or according to the literature method preparation, described literature method is Kraynack for example, E.A; Dalgard, J.E; Gaeta, F.C.A.Tetrahedron Letters, 1998,39,7679-7682, EP153818 is used for 5-fluoro-6-chlorine oxindole etc.
Scheme 3
R 6＝CN
R in reagent VII 6When being strong electron-withdrawing group group, intermediate compound IV can be alternatively by isatin VI and reagent VII preparation.For example, work as R 6Be cyano group, and R 7Be the aryl that replaces, during heteroaryl, in the presence of alkali such as DBU, in methyl alcohol, under the condition that heats, isatin VI can with various R 7The prussiate VII reaction that replaces is to form IV (scheme 3).That 6-replaces or 5, the dibasic isatin VI of 6-raw material is commercially available, or according to the literature method preparation.
Racemic mixture
Intermediate compound IV can be protected, to obtain intermediate VIII.By the use Vinyl chloroformate, tert-Butyl dicarbonate, SEM-Cl, bromotoluene and alkali such as 4-(dimethylamine) pyridine (DMAP), triethylamine, NaH, or LiH according to document program used for a long time, can connect blocking group.Blocking group form and their example of deprotection by Greene, description such as T.W. and summarizing in " Protective Groups in Organic Synthesis, the 2nd edition .John Wiley ﹠amp; Sons Inc.In a similar fashion, in toluene or o-Xylol, under 110 ℃ to 160 ℃ heating and anhydrous condition, intermediate VIII can react with the 2-azepine-divinyl II of the selection of preparation in scheme 1, form intermediate compound I X and IX ', it is shown as racemic mixture (scheme 4) with other minority steric isomer two kinds of enantiomers together as primary product.Intermediate compound I X can change into V (scheme 5) by deprotection reaction.Useful Pg can be a urethanum, t-butyl carbamate (BOC), or trimethylsilyl ethoxyl methyl (SEM).By in methyl alcohol or ethanol, in room temperature, handle IX with alkali such as NaOH, can remove urethanum.In room temperature,, can easily remove t-butyl carbamate (BOC) by handling IX with trifluoroacetic acid.By at first in methylene dichloride, in room temperature, handle with trifluoroacetic acid, then in methyl alcohol, heat with diisopropylethylamine, can realize the deprotection of trimethylsilyl ethoxyl methyl (SEM).
Scheme 5
Figure A200780008564D00341
At R 8Be selected from some group such as low alkyl group, the low alkyl group of replacement when cycloalkyl, the cycloalkyl of replacement, can use alternative synthetic method to obtain arriving the path of compound V or intermediate compound I X.Typically, have and be selected from relevant low-grade alkenyl, or the thiazolinyl that replaces, or cycloalkenyl group, or the R of the cycloalkenyl group that replaces 8Compound V or intermediate compound I X should be at first according to the preparation of the method in scheme 2 or the scheme 4, then be catalytic hydrogenation, to obtain wherein R 8Be corresponding low alkyl group, or the low alkyl group that replaces, or cycloalkyl, or those V or the IX of the cycloalkyl that replaces.With Simmons-Smith reagent (CH 2I 2-Et 2Zn) handle to have and be selected from relevant low-grade alkenyl, or the R of the thiazolinyl that replaces 8Compound V or intermediate compound I X will obtain R 8Be those V or the IX of the corresponding cyclopropyl that replaces.
Under controlled conditions, can carry out selective protection to V, to obtain IX.In the case, useful herein blocking group Pg can be a urethanum, or t-butyl carbamate (BOC) (scheme 6).Be similar in the scheme 4 transformation from IV to VIII, in methylene dichloride, at room temperature or low temperature, by using Vinyl chloroformate, or tert-Butyl dicarbonate and alkali such as 4-(dimethylamine) pyridine (DMAP), can connect blocking group.
Scheme 6
Figure A200780008564D00351
By using Lawesson reagent or other similar related reagent, Compound I X selective conversion can be become the similar thing X of thioamides (scheme 7).Compounds X I can be by the prepared in reaction of X and methyl iodide.
Scheme 7
At mercury reagent such as HgCl 2Or Hg (OAc) 2Exist down, compounds X can also with amine R 9-NH 2, or R 9R 9 'The NH reaction is to form analogue XII (scheme 8).
Scheme 8
Figure A200780008564D00361
Thioamide compound X can also be a useful as intermediates, with preparation condensed triazole analogue.For example, compounds X can with hydrazides EtO (O=C) NHNH2 and mercury reagent such as the HgCl that replace 2Or Hg (OAc) 2Reaction is to form analogue XIV (scheme 9).In toluene, the heating in sealed tube causes the formation of triazole analogue XV.
Figure A200780008564D00362
Similarly, in scheme 10, can prepare compounds X VI.Handle to remove the t-Boc group with trifluoroacetic acid and to cause the formation of intermediate X VII.
Figure A200780008564D00371
The backflow of compounds X VII in formic acid or acetate obtains compounds X VIII (scheme 11).R 10Be hydrogen or methyl.
Scheme 11
Figure A200780008564D00372
Can also be by sodium borohydride or other reductive agent such as BH 3.THF selective reduction compound V is to form compounds X VIII.Compounds X VIII and the suitable alkylating agent R that selects 2-L reaction obtains N-alkylated compound XIX (scheme 12).R 2Be low alkyl group, or the low alkyl group that replaces, and L is good leavings group such as I, Br, Cl, OMs, OTs, OTf.At R 2Be selected from C (=O) R 9, C (=O) NHR 9, C (=O) NR 9R 9 'And C (=O) OR 9Situation under, compounds X VIII and the suitable corresponding acyl chlorides of selecting, isocyanic ester, amino-carbon acyl chlorides, or chloro-formic ester reaction obtain the compounds X IX of N-acidylate.
Scheme 12
Figure A200780008564D00381
Similarly, intermediate compound I X can also be reduced to intermediate X XI by selectivity, alkali exist or not in the presence of, with N-alkylating agent or N-acylating agent processing XXI and carry out the deprotection of the Pg group in XX subsequently, obtain R 2Deutero-analogue XXII (scheme 13).
Scheme 13
Figure A200780008564D00382
By using the separation of super liquid chromatography of chirality (SFC) or chirality HPLC or chiral column stratographic, can be easily with compound V and V ', or intermediate compound I X and IX ' split into the chirality enantiomer of the pure or enrichment of two optically-actives.With with top reaction scheme in the similar mode of method, by V is replaced with its enantiomer V ', or IX IX ' replaced can preparing the chirality enantiomer of compounds X-XXII as raw material accordingly.Compound V and V ', intermediate compound I X and IX ' at first produce as racemic mixture, react under the situation of chiral separation not having subsequently, obtain the corresponding racemic mixture of X-XXII and their enantiomer.With separate V and V ', or the similar mode of the method for IX and IX ', also can be easily with prepare in superincumbent each reaction scheme all these X-XXII and the racemic mixture of their corresponding enantiomers to be separated into optically-active chirality enantiomer pure or enrichment right.
Provide the following example and reference to help understanding the present invention, true scope of the present invention is listed in the appended claim.
Embodiment 1a
Preparation intermediate E/Z-6-chloro-3-(3,3-dimethyl-butylidene)-1, the 3-dihydro-indol-2-one
Figure A200780008564D00391
M.W.249.74 C 14H 16ClNO
((0.21g 2.09mmol) in (Aldrich) mixture in methyl alcohol (20mL), drips tetramethyleneimine (0.15g, 2.09mmol) (Aldrich) to 3-dimethyl-butyraldehyde for 0.26g, 1.49mmol) (Crescent) and 3 to 6-chlorine oxindole.Then, mixture is heated 1h in 100 ℃.Mixture is concentrated, and residuum is distributed between ethyl acetate and water.Organic layer is separated, use Na 2SO 4Drying concentrates, and vacuum-drying, obtains rough E/Z-6-chloro-3-(3,3-dimethyl-butylidene)-1, and the 3-dihydro-indol-2-one is white solid (yield 0.37g, 100%).
Embodiment 1b
Preparation intermediate 1-(3-chloro-phenyl-)-3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.253.81 C 12H 16ClNOSi
Under nitrogen, in room temperature, to 1,1,3,3, (2.18mL 10.5mmol) in (Aldrich), adds n-Butyl Lithium (2.5M, 4.2mL, 10.5mmol) (Aldrich) to the 3-hexamethyldisilazane.With reaction mixture in stirring at room 10 minutes.Add anhydrous tetrahydro furan (30mL) then, then add 3-chloro-phenyl aldehyde (1.19mL, 10.5mmol) (Aldrich).With mixture behind stirring at room 0.5h, drip trimethylsilyl chloride (1.33mL, 10.5mmol) (Aldrich).Then, on the refrigerative ice bath, the temperature of mixture is reduced to 0 ℃.In this mixture, (1.9mL 13.6mmol), follows dripping acetyl chloride (0.97mL, 13.6mmol) solution in diethyl ether (50mL) to add triethylamine with portion.Remove cooling bath, and with mixture in stirring at room 1h.Under nitrogen, mixture is filtered on diatomite rapidly, and filtrate is under reduced pressure concentrated, obtain rough 1-(3-chloro-phenyl-)-3-front three for siloxy--2-azepine-1, the 3-divinyl is yellow glue, and is used for next step under situation about not being further purified.
Similarly change by Ghosez L., Bayard, Ph., Nshimyumukiza, P., Gouverneur, V., Sainte, F., Beaudegnies, R., Rivers, M., Frique-Hesbain, A.-M. and Wynants, C. are reported in Tetrahedron 1995, among the 11021-11042.
Embodiment 1c
Preparation intermediate racemize (2 ' S, 3S, 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(2, the 2-dimethyl propyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00401
M.W.431.36 C 23H 24Cl 2N 2O 2
To the 1-that in embodiment 1b, prepares (3-chloro-phenyl-)-3-front three for siloxy--2-azepine-1,3-divinyl (0.25g, 1mmol) and in the mixture of toluene (4mL), be added in the E/Z-6-chloro-3-(3 for preparing among the embodiment 1a, 3-dimethyl-butylidene)-1, the 3-dihydro-indol-2-one (0.25g, 1mmol).Under nitrogen, reaction mixture is heated 18h in 110 ℃ in sealed tube.Mixture is cooled to room temperature, and adds methyl alcohol (10mL).Mixture concentrated and with residuum by the chromatogram (purifying of EtOAc/ hexane=2:1), obtain racemize (2 ' S, 3S, 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(2, the 2-dimethyl propyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be brown solid (yield 0.15g, 35%).
HRMS (ES +) m/zC 23H 24Cl 2N 2O 2+ H[(M+H) +] calculated value: 431.1288.Measured value: 431.1285
Similarly change by Ghosez, L. and Jnoff, E. is reported in J.Am.Chem.Soc1999, among the 2617-2618.
Embodiment 1d
Preparation racemize (2 ' S, 3S, 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(2, the 2-dimethyl propyl) spiral shells [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00411
M.W.417.38 C 23H 26Cl 2N 2O
In room temperature, in 1h to the racemize that in embodiment 1c, prepares (2 ' S, 3S, 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(2, the 2-dimethyl propyl) spiral shell [3H-indoles-3,3 '-piperidines] (0.028g, 0.065mmol) portioning adds NaBH to-2,6 ' (1H)-diketone in the solution in methyl alcohol (2mL) 4(0.42g, 11mmol).With reaction mixture behind stirring at room 1h, reaction mixture is diluted with ethyl acetate, and water, salt water washing, and concentrates.(EtOAc: the purifying of hexane=1:1) obtains racemize (2 ' S, 3S by chromatogram with residuum, 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(2, the 2-dimethyl propyl) spiral shells [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white solid (yield 0.006g, 21%)
HRMS (ES +) m/z C 23H 26Cl 2N 2O+H[(M+H) +] calculated value: 417.1495.Measured value: 417.1493.
Embodiment 2a
Preparation intermediate E/Z-6-chloro-3-isobutylene-1, the 3-dihydro-indol-2-one
Figure A200780008564D00421
M.W.221.69 C 12H 12ClNO
With with the similar mode of method described in the embodiment 1a, 6-chlorine oxindole (0.85g, 4.8mmol) and 2-methyl-propionic aldehyde (0.42g, 5.8mmol) (Aldrich), tetramethyleneimine (0.41g, 5.8mmol) reaction in methyl alcohol (40mL), obtain E/Z-6-chloro-3-isobutylene-1, the mixture of 3-dihydro-indol-2-one is brown foam (yield 1.0g, 100%).
Embodiment 2b
Preparation intermediate racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-sec.-propyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00422
M.W.403.31 C 21H 20Cl 2N 2O 2
With with the similar mode of method described in the embodiment 1c, E/Z-6-chloro-3-isobutylene-1,3-dihydro-indol-2-one (0.25g, 1.1mmol) with 1-(3-chloro-phenyl-)-3-front three of in embodiment 1b, preparing for siloxy--2-azepine-1,3-divinyl (1.2g, 4.7mmol) in toluene, react, obtain racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-sec.-propyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.25g, 56%).
HRMS (ES +) m/z C 21H 20Cl 2N 2O 2+ H[(M+H) +] calculated value: 403.0975.Measured value: 403.0975.
Embodiment 2c
Preparation intermediate racemize (2 ' S, 3R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-sec.-propyl-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00431
M.W.419.38 C 21H 20Cl 2N 2OS
Racemize (2 ' the S that will in embodiment 2b, prepare, 3R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-sec.-propyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (60mg, 0.15mmol) with 2,4-pair-(4-p-methoxy-phenyl)-1,3-dithia-2,4-two phosphetane 2, (100mg, 0.25mmol) (Aldrich) mixture in toluene (20mL) is in 120 ℃ of heating 0.5h for the 4-disulfide.Mixture is cooled to room temperature, concentrates then.(EtOAc: the purifying of hexane=1:1), (2 ' S 3R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-sec.-propyl-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, is white solid (yield 60mg, 92%) to obtain racemize by chromatogram with residuum.
HRMS (ES +) m/z C 21H 20Cl 2N 2OS+H[(M+H) +] calculated value: 419.0746.Measured value: 419.0744.
Embodiment 2d
The preparation racemize (2 ' S, 3R)-6-chloro-2 '-(3-chloro-phenyl-)-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-4 '-sec.-propyl-6 '-(methylthio group) spiral shell [3H-indoles-3,3 '-pyridine]-2 (1H)-ketone
Figure A200780008564D00432
M.W.433.40 C 22H 22Cl 2N 2OS
Racemize (2 ' the S that will in embodiment 2c, prepare, 3R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-sec.-propyl-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (55mg, 0.13mmol) and methyl iodide (1.7g, 12mmol) (Aldrich) mixture heating up backflow 2h in ethylene dichloride (20mL).Mixture is cooled to room temperature, concentrates then.With residuum by chromatogram (EtOAc: the purifying of hexane=1:2), obtain racemize (2 ' S, 3R)-6-chloro-2 '-(3-chloro-phenyl-)-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-4 '-sec.-propyl-6 '-(methylthio group) spiral shell [3H-indoles-3,3 '-pyridine]-2 (1H)-ketone, be white solid (yield 40mg, 70%).HRMS (ES +) m/z C 22H 22Cl 2N 2OS+H[(M+H) +] calculated value: 433.0933.Measured value: 433.0902.
Embodiment 3a
Preparation intermediate E-6-chloro-3-propylidene-1, the 3-dihydro-indol-2-one
M.W.207.66 C 11H 10ClNO
(2.25g, 12.8mmol) ((10.9g, 90mmol) mixture of (Aldrich) is in 100 ℃ of heating 18h for accelerine for 2.56g, 44mmol) (Aldrich) and N for (Crescent) and propionic aldehyde with 6-chlorine oxindole.Mixture is cooled to room temperature, pours into then in the HCl aqueous solution (1N).With the mixture ethyl acetate extraction.Organic layer is separated, use Na 2SO 4Drying concentrates, and with residuum by chromatogram (EtOAc: the purifying of hexane=1:2), obtain E-6-chloro-3-propylidene-1, the 3-dihydro-indol-2-one is gray solid (yield 1.3g, 49%).
Embodiment 3b
Preparation intermediate racemize (2 ' S, 3S, 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-ethyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00442
M.W.389.28 C 20H 18Cl 2N 2O 2
With with the similar mode of method described in the embodiment 1c, E-6-chloro-3-propylidene-1,3-dihydro-indol-2-one (0.23g, 1mmol) with 1-(3-chloro-phenyl-)-3-front three of in embodiment 1b, preparing for siloxy--2-azepine-1,3-divinyl (1.2g, 4.7mmol) in toluene, react, obtain racemize (2 ' S, 3S, 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-ethyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white solid (yield 0.21g, 50%).
HRMS (ES +) m/z C 20H 18Cl 2N 2O 2+ H[(M+H) +] calculated value: 389.0818.Measured value: 389.0816.
Embodiment 3c
Preparation racemize (2 ' S, 3S, 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-ethyl spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00451
M.W.375.30 C 20H 20Cl 2N 2O
With with the similar mode of method described in the embodiment 1d, the racemize that in embodiment 3b, prepares (2 ' S, 3S, 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-ethyl spiral shell [3H-indoles-3,3 '-piperidines] and-2,6 ' (1H)-diketone (0.086g, 0.22mmol) and NaBH 4In methyl alcohol, react, obtain racemize (2 ' S, 3S, 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-ethyl spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white foam (yield 0.018g, 22%).
HRMS (ES +) m/z C 20H 20Cl 2N 2O+H[(M+H) +] calculated value: 375.1026.Measured value: 375.1023.
Embodiment 4a
Preparation intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-1, the 3-dihydro-indol-2-one
M.W.290.15 C 15H 9Cl 2NO
(16.2g, 92mmol) (12.9g 92mmol) in (Aldrich) mixture in methyl alcohol (109mL), drips tetramethyleneimine (6.55g, 92mmol) (Aldrich) for (Crescent) and 3-chloro-phenyl aldehyde to 6-chlorine oxindole.Then mixture is heated 3h in 70 ℃.After being cooled to 4 ℃, mixture to be filtered, and the throw out that obtains is collected, drying obtains E/Z-6-chloro-3-(3-chloro-benzylidene)-1, and the mixture of 3-dihydro-indol-2-one is faint yellow solid (yield 25.2g, 95%).
Embodiment 4b
Preparation intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester
Figure A200780008564D00462
M.W.362.22 C 18H 13Cl 2NO 3
In 0 ℃, to the E/Z-6-chloro-3-that in embodiment 6a, prepares (3-chloro-benzylidene)-1,3-dihydro-indol-2-one (1.33g, 4.6mmol) solution in methylene dichloride (50mL), add Vinyl chloroformate (0.66mL, 6.9mmol) (Aldrich), then add triethylamine (0.93g, 9.2mmol).Reaction mixture was stirred 30 minutes in 0 ℃.Mixture is poured in the HCl aqueous solution (1N) then.Organic layer is separated, and with the water layer ethyl acetate extraction.Organic layer merged and use Na 2SO 4Drying, and concentrate, obtaining E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester is yellow solid, and is used for next step (yield 1.7g, 100%) under situation about not being further purified.
Embodiment 4c
Preparation intermediate 1-(3-aminomethyl phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure A200780008564D00471
M.W.233.39 C 13H 19NOSi
With with the similar mode of method described in the embodiment 1b, with 3-methyl-phenyl aldehyde (1.30g, 10.5mmol) (Matrix) replaces 3-chloro-phenyl aldehyde as raw material, with with 1,1,1,3,3, and the 3-hexamethyldisilazane (2.18mL, 10.5mmol), just-butyllithium (2.5M, 4.2mL, 10.5mmol), trimethylsilyl chloride (1.33mL, 10.5mmol), triethylamine (1.9mL, 13.6mmol) and Acetyl Chloride 98Min. (0.97mL, 13.6mmol) reaction, obtain 1-(3-aminomethyl phenyl)-3-front three for siloxy--2-azepine-1, the 3-divinyl is yellow glue, and is used for next step under situation about not being further purified.
Embodiment 4d
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-(3-aminomethyl phenyl)-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester
Figure A200780008564D00472
M.W.523.42 C 28H 24Cl 2N 2O 4
To the 1-that in embodiment 4c, prepares (3-aminomethyl phenyl)-3-front three for siloxy--2-azepine-1, in the solution of 3-divinyl in toluene (20mL), be added in E/Z-6-chloro-3-(3-chloro-the benzylidene)-2-oxo-2 for preparing among the embodiment 4b, 3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.3g, 0.83mmol).Reaction mixture under nitrogen, is stirred 1h in 135 ℃ in sealed tube.After solution is cooled to room temperature, add methyl alcohol (50mL), then mixture is concentrated.With residuum by chromatogram (EtOAc:CH 2Cl 2=1:3) purifying obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-(3-aminomethyl phenyl)-2, and 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester is yellow oil (yield 0.5g, 86%).
Embodiment 4e
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00481
M.W.451.35 C 25H 20Cl 2N 2O 2
To the racemize that in embodiment 4d, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2,3-dihydro-2 '-(3-aminomethyl phenyl)-2, (0.5g is 0.96mmol) in the solution in methyl alcohol (30mL) for 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester, adding NaOH (69mg, 1.72mmol).With mixture in stirring at room 0.5h.Except that desolvating and residuum being distributed between the ethyl acetate and the HCl aqueous solution (1N).With the water layer ethyl acetate extraction.Organic layer is merged, concentrate then.With residuum by chromatogram (EtOAc:CH 2Cl 2=1:3) purifying obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, is white solid (yield 0.15g, 35%).
Embodiment 4f
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
M.W.437.37 C 25H 22Cl 2N 2O
With with the similar mode of method described in the embodiment 1d, the racemize that in embodiment 4d, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines] and-2,6 ' (1H)-diketone (0.045g, 0.1mmol) and NaBH 4In methyl alcohol, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white solid (yield 0.014g, 31%).
HRMS (ES +) m/z C 25H 22Cl 2N 2O+H[(M+H) +] calculated value: 437.1182.Measured value: 437.1178.
Embodiment 5a
Preparation intermediate 1-(3-fluorophenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure A200780008564D00492
M.W.237.35 C 12H 16FNOSi
With with the similar mode of method described in the embodiment 1b, with 3-fluoro-phenyl aldehyde (1.11mL, 10.5mmol) (Fluka) replaces 3-chloro-phenyl aldehyde as raw material, with with 1,1,1,3,3, and the 3-hexamethyldisilazane (2.18mL, 10.5mmol), just-butyllithium (2.5M, 4.2mL, 10.5mmol), trimethylsilyl chloride (1.33mL, 10.5mmol), triethylamine (1.9mL, 13.6mmol) and Acetyl Chloride 98Min. (0.97mL, 13.6mmol) reaction, obtain 1-(3-fluorophenyl)-3-front three for siloxy--2-azepine-1, the 3-divinyl is yellow glue, and is used for next step under situation about not being further purified.
Embodiment 5b
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluorophenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester
Figure A200780008564D00501
M.W.527.38 C 27H 21Cl 2FN 2O 4
With with the similar mode of method described in the embodiment 4d, the E/Z-6-chloro-3-that in embodiment 4b, prepares (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.25g, 0.69mmol) with 1-(3-fluorophenyl)-3-front three of in embodiment 6a, preparing for siloxy--2-azepine-1, the 3-divinyl reacts in toluene, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluorophenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester, be yellow oil (yield 0.35g, 97%).
Embodiment 5c
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00502
M.W.455.314 C 24H 17Cl 2FN 2O 2
With with the similar mode of method described in the embodiment 4e, with racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluorophenyl)-2,3-dihydro-2, (0.35g is 0.66mmol) with NaOH (48mg for 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester, 1.19mmol) reaction, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (yield 0.15g, 50%).
HRMS (ES +) m/z C 24H 17Cl 2FN 2O 2+ H[(M+H) +] calculated value: 451.0975.Measured value: 451.0976.
Embodiment 5d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00511
M.W.441.34 C 24H 19Cl 2FN 2O
With with the similar mode of method described in the embodiment 1d, racemize (2 ' R, the 3R that will in embodiment 5c, prepare, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines] and-2,6 ' (1H)-diketone (0.046g, 0.1mmol) and NaBH 4In methyl alcohol, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white solid (yield 0.020g, 46%).
HRMS (ES +) m/z C 24H 19Cl 2FN 2O+H[(M+H) +] calculated value: 441.0931.Measured value: 441.0928.
Embodiment 6a
Preparation intermediate E/Z-3-benzylidene-6-chloro-1, the 3-dihydro-indol-2-one
Figure A200780008564D00512
M.W.255.71 C 15H 10ClNO
With with the similar mode of method described in the embodiment 1a, with 6-chlorine oxindole (1.0g, 5.7mmol) and phenyl aldehyde (0.6g, 5.7mmol) (Aldrich) and tetramethyleneimine (0.4g, 5.7mmol) in methyl alcohol, react, obtain E-and Z-3-benzylidene-6-chloro-1, the mixture of 3-dihydro-indol-2-one, be yellow solid (yield 1.5g, 100%).
Embodiment 6b
Preparation intermediate E/Z-3-benzylidene-6-chloro-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester
Figure A200780008564D00521
M.W.327.77 C 18H 14ClNO 3
With with the similar mode of method described in the embodiment 4b, with E/Z-3-benzylidene-6-chloro-1,3-dihydro-indol-2-one (1.5g, 5.87mmol) with Vinyl chloroformate (0.83mL, 8.8mmol) and triethylamine (1.64mL 12mmol) reacts in methylene dichloride, obtain E/Z-3-benzylidene-6-chloro-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester is yellow solid (yield 2.0g, 100%).
Embodiment 6c
Preparation intermediate racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00522
M.W.437.33 C 24H 18Cl 2N 2O 2
To the 1-that in embodiment 1b, prepares (3-chloro-phenyl-)-3-front three for siloxy--2-azepine-1, in the solution of 3-divinyl in toluene (30mL), be added in the E/Z-3-benzylidene-6-chloro-2-oxo-2 for preparing among the embodiment 6b, 3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.4g, 1.22mmol).Reaction mixture under nitrogen, is stirred 1h in 140 ℃ in sealed tube.After solution is cooled to room temperature, add methyl alcohol (40mL).The short pad of reaction mixture by diatomite glue filtered, and wash with ethyl acetate.Filtrate is concentrated.Residuum is dissolved in the methyl alcohol (30mL), and the NaOH solution of adding 1N (5mL, 5mmol).Reaction mixture in stirring at room 0.5h, is concentrated mixture then.With residuum by chromatogram (EtOAc:CH 2Cl 2=1:4) purifying obtains racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, is yellow oil (yield 0.5g, 100%).
HRMS (ES +) m/z C 24H 18Cl 2N 2O 2+ H[(M+H) +] calculated value: 437.0818.Measured value: 437.0817.
Embodiment 6d
Preparation racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
M.W.423.35 C 24H 20Cl 2N 2O
With with the similar mode of method described in the embodiment 1d, racemize (2 ' S, the 3S that will in embodiment 6c, prepare, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines] and-2,6 ' (1H)-diketone (52.1mg, 0.12mmol) and NaBH 4(45.1mg, 1.2mmol) reaction in methyl alcohol (2mL) obtains racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, is white solid (yield 15.8mg, 31.1%).
HRMS (ES +) m/z C 24H 20Cl 2N 2O+H[(M+H) +] calculated value: 423.1026.Measured value: 423.1025.
Embodiment 7a
Preparation intermediate 1-(3-chloro-phenyl-)-4-methyl-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure A200780008564D00532
M.W.267.83 C 13H 18ClNOSi
With with the similar mode of method described in the embodiment 1b, with propionyl chloride (1.2g, 13.mmol) (Aldrich) is as the raw material replacing acetyl chloride, with with 1,1,3,3,3-hexamethyldisilazane (1.61g, 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), 3-chloro-phenyl aldehyde (1.4g, 10mmol) (Aldrich), trimethylsilyl chloride (1.1g, 10mmol) and triethylamine (1.36g, 13mmol) reaction obtains 1-(3-chloro-phenyl-)-4-methyl-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 7b
Preparation intermediate racemize (2 ' S, 3S, 4 ' R, 5 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-5 '-methyl-4 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00541
M.W.451.36 C 25H 20Cl 2N 2O 2
With with the similar mode of method described in the embodiment 6c, the E/Z-3-benzylidene that will in embodiment 6b, prepare-6-chloro-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.32g, 0.98mmol) with 1-(3-chloro-phenyl-)-4-methyl-3-front three of in embodiment 7a, preparing for siloxy--2-azepine-1,3-divinyl (1.5g, 5.6mmol) in toluene, react, then with 2N NaOH solution (4mL, 8mmol) in methyl alcohol, react, obtain racemize (2 ' S, 3S, 4 ' R, 5 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-5 '-methyl-4 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white foam (yield 0.21g, 48%).
HRMS (ES +) m/z C 25H 20Cl 2N 2O 2+ H[(M+H) +] calculated value: 451.0975.Measured value: 451.0972.
Embodiment 7c
Preparation racemize (2 ' R, 3R, 4 ' S, 5 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00551
M.W.451.40 C 26H 24Cl 2N 2O
With with the similar mode of method described in the embodiment 1d, racemize (2 ' the R that will in embodiment 7b, prepare, 3R, 4 ' S, 5 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines] and-2,6 ' (1H)-diketone (0.21g, 0.45mmol) and NaBH 4(170.2mg, 4.5mmol) reaction in methyl alcohol (2mL) obtains racemize (2 ' R, 3R, 4 ' S, 5 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white solid (yield 13.6mg, 6.7%).
HRMS (ES +) m/z C 26H 24Cl 2N 2O+H[(M+H) +] calculated value: 451.1339.Measured value: 451.1337.
Embodiment 8a
Preparation intermediate 1-(3-p-methoxy-phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure A200780008564D00552
M.W.249.39 C 13H 19NO 2Si
With with the similar mode of method described in the embodiment 1b, with 3-methoxyl group-phenyl aldehyde (1.3g, 9.5mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with with 1,1,1,3,3, and the 3-hexamethyldisilazane (1.53g, 9.5mmol), just-butyllithium (2.5M, 3.8mL, 9.5mmol), trimethylsilyl chloride (1.2mL, 9.5mmol), triethylamine (1.72mL, 12.4mmol) and Acetyl Chloride 98Min. (0.88mL, 12.4mmol) reaction, obtain 1-(3-p-methoxy-phenyl)-3-front three for siloxy--2-azepine-1, the 3-divinyl is yellow glue, and is used for next step under situation about not being further purified.
Embodiment 8b
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00561
M.W.467.36 C 25H 20Cl 2N 2O 3
With with the similar mode of method described in the embodiment 6c, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.23g, 0.63mmol) with 1-(3-p-methoxy-phenyl)-3-front three of in embodiment 8a, preparing for siloxy--4-methyl-2-azepine-1,3-divinyl (2g, 8.0mmol) in toluene, react, then with 2N NaoH solution (4mL, 8mmol) in methyl alcohol, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (yield 0.2g, 69%).
HRMS (ES +) m/z C 25H 20Cl 2N 2O 3+ H[(M+H) +] calculated value: 467.0924.Measured value: 467.0925.
Embodiment 8c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00562
M.W.453.37 C 25H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 1d, racemize (2 ' R, the 3R that will in embodiment 8b, prepare, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines] and-2,6 ' (1H)-diketone (0.11g, 0.24mmol) and NaBH 4In methyl alcohol, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white solid (yield 0.018g, 17%).
HRMS (ES +) m/z calculated value C 25H 22Cl 2N 2O 2+ H[(M+H) +]: 453.1131.Measured value: 453.1125.
Embodiment 9a
Preparation intermediate 1-(3-cyano-phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.244.37 C 13H 16N 2OSi
With with the similar mode of method described in the embodiment 1b, with 3-cyano group-phenyl aldehyde (1.2g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with with 1,1,1,3,3, and the 3-hexamethyldisilazane (1.62g, 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.3g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(3-cyano-phenyl)-3-front three for siloxy--2-azepine-1, the 3-divinyl is yellow glue, and is used for next step under situation about not being further purified.
Embodiment 9b
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-cyano-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00572
M.W.462.34 C 25H 17Cl 2N 3O 2
With with the similar mode of method described in the embodiment 6c, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.42g, 1.2mmol) with 1-(3-cyano-phenyl)-3-front three of in embodiment 9a, preparing for siloxy--2-azepine-1,3-divinyl (2.0g, 8.18mmol) in toluene, react, then with 2N NaOH solution (5mL, 10mmol) in methyl alcohol, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-cyano-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be white foam (yield 0.11g, 20%).
HRMS (ES +) m/z C 25H 17Cl 2N 3O 2+ H[(M+H) +] calculated value: 462.0771 measured values: 462.0771.
Embodiment 9c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-cyano-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00581
M.W.448.36 C 25H 19Cl 2N 3O
With with the similar mode of method described in the embodiment 1d, (2 ' R, the 3R that will in 9b, prepare, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-cyano-phenyl) spiral shell [3H-indoles-3,3 '-piperidines] and-2,6 ' (1H)-diketone (0.05g, 0.11mmol) and NaBH 4In methyl alcohol, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-cyano-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white foam (Yield:0.026g, 53%).
HRMS (ES +) m/z C 25H 19Cl 2N 3O+H[(M+H) +] calculated value: 448.0978.Measured value: 448.0978.
Embodiment 10a
Preparation intermediate 1-(2, the 3-3,5-dimethylphenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure A200780008564D00591
M.W.247.42 C 14H 21NOSi
With with the similar mode of method described in the embodiment 1b, with 2,3-dimethyl-phenyl aldehyde (1.34g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1,3,3,3-hexamethyldisilazane (1.61g, 10mmol), just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol), and triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(2, the 3-3,5-dimethylphenyl)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 10b
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 3-3,5-dimethylphenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00592
M.W.465.38 C 26H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 6c, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.3g, 0.83mmol) with the 1-(2 that in embodiment 10a, prepares, the 3-3,5-dimethylphenyl)-the 3-front three is for siloxy--2-azepine-1, (2.4g 9.72mmol) reacts in toluene the 3-divinyl, then with NaOH (0.2g, 5mmol) in methyl alcohol, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 3-3,5-dimethylphenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (yield 0.20g, 53%).
HRMS (ES +) m/z C 26H 22Cl 2N 2O 2+ H[(M+H) +] calculated value: 465.1131.Measured value: 465.1131.
Embodiment 10c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 3-3,5-dimethylphenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00601
M.W.451.40 C 26H 24Cl 2N 2O
With with the similar mode of method described in the embodiment 1d, racemize (2 ' the R that will in embodiment 35b, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 3-3,5-dimethylphenyl) spiral shell [3H-indoles-3,3 '-piperidines] and-2,6 ' (1H)-diketone (72.9mg, 0.16mmol) and NaBH 4(68.1mg, 1.6mmol) reaction in methyl alcohol (2mL) obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 3-3,5-dimethylphenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white solid (yield 8.2mg, 12%).
HRMS (ES +) m/z C 26H 24Cl 2N 2O+H[(M+H) +] calculated value: 451.1339.Measured value: 451.1334.
Embodiment 11a
Preparation intermediate 1-[2-(trifluoromethyl)-phenyl]-the 3-front three is for siloxy--2-azepine-1,3-butadiene
Figure A200780008564D00602
M.W.287.36 C 13H 16F 3NOSi
With with the similar mode of method described in the embodiment 1b, with 2-(trifluoromethyl)-phenyl aldehyde (1.75g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with with 1,1,3,3,3-hexamethyldisilazane (1.6g, 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction obtains 1-[2-(trifluoromethyl)-phenyl]-the 3-front three is for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 11b
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00611
M.W.505.33 C 25H 17Cl 2F 3N 2O 2
With with the similar mode of method described in the embodiment 6c, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.5g, 1.38mmol) with 1-[2-(trifluoromethyl)-phenyl of in embodiment 11a, preparing]-the 3-front three is for siloxy--2-azepine-1,3-divinyl (3.2g, 11.1mmol) in toluene, react, then with NaOH (0.2g, 5mmol) in methyl alcohol, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be pale solid (yield 0.45g, 64%).
HRMS (ES +) m/z C 25H 17Cl 2F 3N 2O 2+ H[(M+H) +] calculated value: 505.0692.Measured value: 505.0688.
Embodiment 11c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(trifluoromethyl)-phenyl)] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00621
M.W.491.34 C 25H 19Cl 2F 3N 2O
With with the similar mode of method described in the embodiment 1d, racemize (2 ' the R that will in embodiment 11b, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.067g, 0.13mmol) and NaBH 4In methyl alcohol, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(trifluoromethyl)-phenyl)] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white solid (yield 0.008g, 13%).
HRMS (ES +) m/z C 25H 19Cl 2F 3N 2O+H[(M+H) +] calculated value: 491.0900.Measured value: 491.0894.
Embodiment 12a
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-6 '-sulfo--2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00622
M.W.521.39 C 25H 17Cl 2F 3N 2OS
With with the similar mode of method described in the embodiment 2c, racemize (2 ' the R that will in embodiment 11b, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.4g, 0.79mmol) with 2,4-pair-(4-p-methoxy-phenyl)-1,3-dithia-2,4-two phosphetane 2,4-disulfide (0.4g, 0.99mmol) in toluene, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-6 '-sulfo--2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (yield 0.15g, 36%).
HRMS (ES +) m/z C 25H 17Cl 2F 3N 2OS+H[(M+H) +] calculated value: 521.0464.Measured value: 521.0458.
Embodiment 12b
The preparation racemize (2 ' S, 3R)-6-chloro-4 '-(3-chloro-phenyl-)-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-6 '-(methylthio group)-2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-pyridine]-2 (1H)-ketone
Figure A200780008564D00631
M.W.535.42 C 26H 19Cl 2F 3N 2OS
With with the similar mode of method described in the embodiment 38, racemize (2 ' the R that will in embodiment 41, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-6 '-sulfo--2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (0.15g, 0.29mmol) and methyl iodide (2.5g, 17.6mmol) in ethylene dichloride, react, obtain racemize (2 ' S, 3R)-6-chloro-4 '-(3-chloro-phenyl-)-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-6 '-(methylthio group)-2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-pyridine]-2 (1H)-ketone, be white solid (yield 0.11g, 73%).
HRMS (ES +) m/z C 26H 19Cl 2F 3N 2OS+H[(M+H) +] calculated value: 535.0620.Measured value: 535.0611.
Embodiment 13a
Preparation intermediate 1-[5-fluoro-2-(trifluoromethyl)-phenyl]-the 3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.305.35 C 13H 15F 4NOSi
With with the similar mode of method described in the embodiment 1b, with 5-fluoro-2-(trifluoromethyl)-phenyl aldehyde (1.9g, 10mmol) (Matrix) replaces 3-chloro-phenyl aldehyde as raw material, with with 1,1,3,3,3-hexamethyldisilazane (1.61g, 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction obtains 1-[5-fluoro-2-(trifluoromethyl)-phenyl]-the 3-front three is for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 13b
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00641
M.W.523.32 C 25H 16Cl 2F 4N 2O 2
With with the similar mode of method described in the embodiment 6c, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.41g, 1.13mmol) with 1-[5-fluoro-2-(trifluoromethyl)-phenyl of in embodiment 13a, preparing]-the 3-front three is for siloxy--2-azepine-1,3-divinyl (2.9g, 9.5mmol) in toluene, react, then with NaOH (0.2g, 5mmol) in methyl alcohol, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, be pale solid (yield 0.31g, 52%).
HRMS (ES +) m/z C 25H 16Cl 2F 4N 2O 2+ H[(M+H) +] calculated value: 523.0598.Measured value: 523.0593.
Embodiment 13c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00651
M.W.509.33 C 25H 18Cl 2F 4N 2O
With with the similar mode of method described in the embodiment 6c, racemize (2 ' the R that will in embodiment 13b, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (104.2mg, 0.20mmol) and NaBH 4(117mg, 3.1mmol) reaction in methyl alcohol (2mL) obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white solid (yield 30.1mg, 29.7%).
HRMS (ES +) m/z C 25H 18Cl 2F 4N 2O+H[(M+H) +] calculated value: 509.0805.Measured value: 509.0798.
Embodiment 14a
Preparation intermediate 1-(5-fluoro-2-aminomethyl phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.251.38 C 13H 18FNOSi
With with the similar mode of method described in the embodiment 1b, with 5-fluoro-2-methyl-phenyl aldehyde (1.38g, 10mmol) (Platte) replaces 3-chloro-phenyl aldehyde as raw material, with with 1,1,1,3,3, and the 3-hexamethyldisilazane (1.61g, 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(5-fluoro-2-aminomethyl phenyl)-3-front three for siloxy--2-azepine-1, the 3-divinyl is yellow glue, and is used for next step under situation about not being further purified.
Embodiment 14b
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00661
M.W.469.35 C 25H 19Cl 2FN 2O 2
With with the similar mode of method described in the embodiment 6c, the E/Z-6-chloro-3-that will in embodiment 4b, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.25g, 0.69mmol) with 1-(5-fluoro-2-aminomethyl phenyl)-3-front three of in embodiment 14a, preparing for siloxy--2-azepine-1,3-divinyl (2.5g, 9.9mmol) in toluene, react, (1N, 5mL 5mmol) react in methyl alcohol with NaOH then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (yield 0.13g, 41%).HRMS (ES +) m/zC 25H 19Cl 2FN 2O 2+ H[(M+H) +] calculated value: 469.0881.Measured value: 469.0881.
Embodiment 14c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00662
M.W.455.36 C 25H 21Cl 2FN 2O
With with the similar mode of method described in the embodiment 1d, racemize (2 ' the R that will in embodiment 14b, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (80.1mg, 0.17mmol) and NaBH 4(117mg, 3.1mmol) reaction in methyl alcohol (2mL) obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white solid (yield 23.1mg, 29.7%).
HRMS (ES +) m/z C 25H 21Cl 2FN 2O+H[(M+H) +] calculated value: 455.1088.Measured value: 455.1091.
Embodiment 15a
Preparation intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester
M.W.390.27 C 20H 17Cl 2NO 3
In room temperature, the E/Z-6-chloro-3-that in embodiment 4a, prepares (3-chloro-benzylidene)-1,3-dihydro-indol-2-one (1g, 3.4mmol) in the solution in methylene dichloride (50mL), add tert-Butyl dicarbonate (1.5g, 6.9mmol) (Aldrich), then add 4-dimethylaminopyridine (1g, 8.2mmol).With reaction mixture in stirring at room 1h.Then mixture is concentrated and with residuum by chromatogram purification, obtain E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester is orange solids (yield 1.3g, 96%).
Embodiment 15b
Preparation intermediate 1-(2,4 difluorobenzene base)-3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.255.34 C 12H 15F 2NOSi
With with the similar mode of method described in the embodiment 1b, with 2,4-two fluoro-phenyl aldehyde (1.4g, 10mmol) (Aldrich) replaces the 3-chlorobenzaldehyde as raw material, with 1,1,3,3,3-hexamethyldisilazane (1.6g, 10mmol), just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol), and triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(2,4 difluorobenzene base)-3-front three for siloxy--2-azepine-1,3-butadiene, be yellow glue, and under situation about not being further purified, be used for next step.
Embodiment 15c
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,4 difluorobenzene base) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00681
M.W.473.31 C 24H 16Cl 2F 2N 2O 2
To the 1-(2 that in embodiment 15b, prepares, the 4-difluorophenyl)-the 3-front three is for siloxy--2-azepine-1,3-divinyl (2.4g, 9.40mmol) in the solution in toluene (30mL), be added in E/Z-6-chloro-3-(3-chlorine the benzylidene)-2-oxo-2 for preparing among the embodiment 15a, 3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.3g, 0.77mmol).Reaction mixture under nitrogen, is stirred 0.5h in 140 ℃ in sealed tube.After solution is cooled to room temperature, add methyl alcohol (10mL).The short pad of reaction mixture by diatomite glue filtered, and wash with ethyl acetate.Filtrate is concentrated.Residuum is dissolved in the methylene dichloride (20mL), and adds trifluoroacetic acid (15mL).With reaction mixture behind stirring at room 1h, mixture is concentrated.With residuum at saturated NaHCO 3Distribute between solution and the ethyl acetate.With the water layer ethyl acetate extraction.With the organic layer Na that merges 2SO 4Dry and concentrated.(EtOAc: the purifying of hexane=2:1) obtains racemize (2 ' R, 3R by chromatogram with residuum, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,4 difluorobenzene base) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is pale solid (yield 0.23g, 63.9%).
HRMS (ES +) m/z C 24H 16Cl 2F 2N 2O 2+ H[(M+H) +] calculated value: 473.0630.Measured value: 473.0630.
Embodiment 15d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,4 difluorobenzene base) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00691
M.W.459.33 C 24H 18Cl 2F 2N 2O
With with the similar mode of method described in the embodiment 1d, racemize (2 ' the R that will in embodiment 15c, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 4-difluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines] and-2,6 ' (1H)-diketone (211.2mg, 0.45mmol) and NaBH 4(170mg, 4.5mmol) reaction in methyl alcohol (2mL) obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,4 difluorobenzene base) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white solid (yield 30.6mg, 14.9%).
HRMS (ES +) m/z C 24H 18Cl 2F 2N 2O+H[(M+H) +] calculated value: 459.0837.Measured value: 459.0835.
Embodiment 16a
Preparation intermediate 1-(5-fluoro-2-p-methoxy-phenyl)-3-front three is for siloxy--2-azepine-1,3-divinyl
Figure A200780008564D00692
M.W.267.38 C 13H 18FNO 2Si
With with the similar mode of method described in the embodiment 1b, with 5-fluoro-2-methoxyl group-phenyl aldehyde (1.5g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with with 1,1,1,3,3, and the 3-hexamethyldisilazane (1.6g, 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(5-fluoro-2-p-methoxy-phenyl)-3-front three for siloxy--2-azepine-1, the 3-divinyl is yellow glue, and is used for next step under situation about not being further purified.
Embodiment 16b
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00701
M.W.485.36 C 25H 19Cl 2FN 2O 3
With with the similar mode of method described in the embodiment 15c, the E/Z-6-chloro-3-that will in embodiment 15a, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.3g, 0.77mmol) with 1-(5-fluoro-2-p-methoxy-phenyl)-3-front three of in embodiment 16a, preparing for siloxy--2-azepine-1,3-divinyl (2.4g, 9.0mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (15mL) then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (yield 0.18g, 49%).
HRMS (ES +) m/z C 25H 19Cl 2FN 2O 3+ H[(M+H) +] calculated value: 485.0830.Measured value: 485.0827.
Embodiment 16c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00711
M.W.471.36 C 25H 21Cl 2FN 2O 2
With with the similar mode of method described in the embodiment 1d, racemize (2 ' the R that will in embodiment 16b, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (154.3mg, 0.32mmol) and NaBH 4(121.0mg, 3.2mmol) reaction in methyl alcohol (2mL) obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white solid (yield 21.5mg, 14.3%).
HRMS (ES +) m/z C 25H 21Cl 2FN 2O 2+ H[(M+H) +] calculated value: 471.1037.Measured value: 471.1036.
Embodiment 17a
Preparation intermediate 1-(1-naphthyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.269.42 C 16H 19NOSi
With with the similar mode of method described in the embodiment 1b, with naphthalene-1-formaldehyde (1.6g, 10mmol) (Lancaster) replaces 3-chloro-phenyl aldehyde as raw material, with with 1,1,1,3,3, and the 3-hexamethyldisilazane (1.6g, 10mmol), n-Butyl Lithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(1-naphthyl)-3-front three for siloxy--2-azepine-1, the 3-divinyl is yellow glue, and is used for next step under situation about not being further purified.
Embodiment 17b
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-naphthyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00721
M.W.487.39 C 28H 10Cl 2N 2O 2
With with the similar mode of method described in the embodiment 15c, the E/Z-6-chloro-3-that will in embodiment 15a, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.3g, 0.77mmol) with 1-(1-naphthyl)-3-front three of in embodiment 17a, preparing for siloxy--2-azepine-1,3-divinyl (2.7g, 10.0mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (15mL) then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-naphthyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (yield 0.21g, 57%).
HRMS (ES +) m/z C 28H 10Cl 2N 2O 2+ H[(M+H) +] calculated value: 487.0975.Measured value: 487.0975.
Embodiment 17c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-naphthyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00722
M.W.473.41 C 28H 22Cl 2N 2O
With with the similar mode of method described in the embodiment 1d, racemize (2 ' R, the 3R that will in embodiment 17b, prepare, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-naphthyl) spiral shell [3H-indoles-3,3 '-piperidines] and-2,6 ' (1H)-diketone (201.3mg, 0.41mmol) and NaBH 4(155.0mg, 4.1mmol) reaction in methyl alcohol (2mL) obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-naphthyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white solid (yield 51.5mg, 26.3%).
HRMS (ES +) m/z C 28H 22Cl 2N 2O+H[(M+H) +] calculated value: 473.1182.Measured value: 473.1182.
Embodiment 18a
Preparation intermediate 1-(3-pyridyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
M.W.220.35 C 11H 16N 2OSi
With with the similar mode of method described in the embodiment 1b, with pyridine-3-formaldehyde (1.1g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with with 1,1,1,3,3, and the 3-hexamethyldisilazane (1.6g, 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(3-pyridyl)-3-front three for siloxy--2-azepine-1, the 3-divinyl is yellow glue, and is used for next step under situation about not being further purified.
Embodiment 18b
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-pyridyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00732
M.W.438.32 C 23H 17Cl 2N 3O 2
With with the similar mode of method described in the embodiment 15c, the E/Z-6-chloro-3-that will in embodiment 15a, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.3g, 0.77mmol) with 1-(3-pyridyl)-3-front three of in embodiment 18a, preparing for siloxy--2-azepine-1,3-divinyl (2.1g, 9.5mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (10mL) then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-pyridyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.21g, 62%).
HRMS (ES +) m/z C 23H 17Cl 2N 3O 2+ H[(M+H) +] calculated value: 438.0771.Measured value: 438.0771.
Embodiment 18c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-pyridyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
M.W.424.33 C 23H 19Cl 2N 3O
With with the similar mode of method described in the embodiment 1d, racemize (2 ' R, the 3R that will in embodiment 18b, prepare, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-pyridyl) spiral shell [3H-indoles-3,3 '-piperidines] and-2,6 ' (1H)-diketone (180.3mg, 0.41mmol) and NaBH 4(126mg, 3.3mmol) reaction in methyl alcohol (2mL) obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-pyridyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white solid (yield 50.1mg, 29.4%).
HRMS (ES +) m/z C 23H 19Cl 2N 3O+H[(M+H) +] calculated value: 424.0978.Measured value: 424.0977.
Embodiment 19a
Preparation intermediate 1-(3, the 4-difluorophenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure A200780008564D00751
M.W.255.34 C 12H 15F 2NOSi
With with the similar mode of method described in the embodiment 1b, with 3,4-two fluoro-phenyl aldehyde (1.4g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1,1,3,3, the 3-hexamethyldisilazane (1.6g, 10mmol), n-Butyl Lithium (2.5M, 4mL, 10mmol), and trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(3, the 4-difluorophenyl)-the 3-front three is for siloxy--2-azepine-1, the 3-divinyl is orange glue, and is used for next step under situation about not being further purified.
Embodiment 19b
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.473.31 C 24H 16Cl 2F 2N 2O 2
With with the similar mode of method described in the embodiment 15b, the E/Z-6-chloro-3-that will in embodiment 15a, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.3g, 0.77mmol) with the 1-(3 that in embodiment 62a, prepares, the 4-difluorophenyl)-the 3-front three is for siloxy--2-azepine-1,3-divinyl (2.1g, 8.2mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (10mL) then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.4g, 100%).
HRMS (ES +) m/z C 24H 16Cl 2F 2N 2O 2+ H[(M+H) +] calculated value: 473.0630.Measured value: 473.0631.
Embodiment 19c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3,4-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00761
M.W.459.33 C 24H 18Cl 2F 2N 2O
With with the similar mode of method described in the embodiment 1d, racemize (2 ' R, the 3R that will in embodiment 19b, prepare, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (158mg, 0.33mmol) and NaBH 4(126mg, 3.3mmol) reaction in methyl alcohol (2mL) obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white solid (yield 48.6mg, 32.1%).
HRMS (ES +) m/z C 24H 18Cl 2F 2N 2O+H[(M+H) +] calculated value: 459.0837.Measured value: 459.0835.
Embodiment 20a
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl)-6 '-sulfo-spiral shells [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00762
M.W.489.37 C 24H 16Cl 2F 2N 2OS
With with the similar mode of method described in the embodiment 2d, racemize (2 ' the R that will in embodiment 19b, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.3g, 0.63mmol) with 2,4-pair-(4-p-methoxy-phenyl)-1,3-dithia-2,4-two phosphetane2, (0.32g 0.77mmol) reacts in toluene the 4-disulfide, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (yield 0.29g, 94%).
HRMS (ES +) m/z C 24H 16Cl 2F 2N 2OS+H[(M+H) +] calculated value: 489.0401.Measured value: 489.0402.
Embodiment 20b
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's ethyl ester
Figure A200780008564D00771
M.W.559.40 C 27H 22Cl 2F 2N 4O 3
To the racemize that in embodiment 20a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines] (0.24g 0.49mmol) in the solution in tetrahydrofuran (THF) (20mL), adds carbazic acid ethyl ester (0.1g to-2 (1H)-ketone, 0.99mmol) (Aldrich) and mercuric acetate (0.24g, 0.76mmol).With reaction mixture behind stirring at room 2h, reaction mixture is filtered by diatomaceous short pad.Filtrate concentrated and with residuum by chromatogram (EtOAc) purifying, obtain racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's ethyl ester, be white solid (yield 0.21g, 77.8%).
Embodiment 20c
Preparation racemize (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(3, the 4-difluorophenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone
Figure A200780008564D00781
M.W.513.33 C 25H 16Cl 2F 2N 4O 2
Racemize ((2 ' the R that will in embodiment 20a, prepare, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3, the 4-difluorophenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-the 6-subunit] (0.17g, 0.30mmol) solution in toluene (20mL) heats 3h in 150 ℃ to hydrazine carboxylic acid's ethyl ester in sealed tube.After solution is cooled to room temperature,, obtain racemize (5 ' R except that desolvating and residuum being ground with the EtOAc/ hexane, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(3, the 4-difluorophenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone, be white solid (yield: 0.11g, 70.5%)
HRMS (ES +) m/z C 25H 16Cl 2F 2N 4O 2+ H[(M+H) +] calculated value: 513.0691 measured values: 513.0689.
Embodiment 21a
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00782
M.W.485.41 C 25H 19Cl 2FN 2OS
With with the similar mode of method described in the embodiment 2d, racemize (2 ' the R that will in embodiment 14b, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.1g, 0.21mmol) with 2,4-pair-(4-p-methoxy-phenyl)-1,3-dithia-2,4-two phosphetane2,4-disulfide (0.2g, 0.49mmol) in toluene, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white solid (yield 0.095g, 92%).
HRMS (ES +) m/z C 25H 19Cl 2FN 2OS+H[(M+H) +] calculated value: 485.0652.Measured value: 485.0648.
Embodiment 21b
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's ethyl ester
Figure A200780008564D00791
M.W.555.44 C 28H 25Cl 2FN 4O 3
With with the similar mode of method described in the embodiment 20b, (2 ' the R that will in embodiment 55, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (0.17g, 0.35mmol) and carbazic acid ethyl ester (0.15g, 1.49mmol), mercuric acetate (0.26g, 0.82mmol) and triethylamine (0.17g, 1.69mmol) reaction in tetrahydrofuran (THF) (20mL) obtains racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's ethyl ester, be white solid (yield 0.14g, 73.7%).
Embodiment 21c
Preparation racemize (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(5-fluoro-2-aminomethyl phenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone
Figure A200780008564D00792
M.W.509.37 C 26H 19Cl 2FN 4O 2
Racemize ((2 ' the R that will in embodiment 21b, prepare, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-the 6-subunit] (0.11g, 1.98mmol) solution in toluene (20mL) heats 4h in 165 ℃ to hydrazine carboxylic acid's ethyl ester in sealed tube.After solution is cooled to room temperature,, obtain racemize (5 ' R except that desolvating and residuum being ground with the EtOAc/ hexane, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(5-fluoro-2-aminomethyl phenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone, be white solid (yield: 0.058g, 58%)
HRMS (ES +) m/z C 26H 19Cl 2FN 4O 2+ H[(M+H) +] calculated value: 509.0942 measured values: 509.0943.
Embodiment 22a
Preparation intermediate 2,3-two fluoro-6-methyl-phenyl aldehydes
Figure A200780008564D00801
M.W.156.13 C 8H 6F 2O
In-78 ℃, to 1, (5.0g, 39mmol) in the solution in tetrahydrofuran (THF) (200mL), during 15min, (24mL, 1.8M is in THF, 43mmol) to drip lithium diisopropylamine for 2-two fluoro-4-methyl-benzene.Mixture is stirred other 20min in-78 ℃.Add N with portion then, and N-dimethyl-methane amide (3.6mL, 47mmol).
In-78 ℃ of stirring 10min, (9.4g, 1.56mmol) quencher then add entry (37.6mL) to use acetate then with mixture.Mixture is distributed between ethyl acetate and water.Organic layer is separated, concentrate.With residuum by chromatogram (EtOAc: the purifying of hexane=1:1), obtain 2,3-two fluoro-6-methyl-phenyl aldehydes are colorless oil (yield: 3.5g, 57.5%).
Embodiment 22b
Preparation intermediate 1-(2,3-two fluoro-6-aminomethyl phenyls)-3-front three is for siloxy--2-azepine-1,3-divinyl
M.W.269.37 C 13H 17F 2NOSi
With with the similar mode of method described in the embodiment 1b, will in embodiment 78a, prepare 2,3-two fluoro-6-methyl-phenyl aldehydes replace 3-chloro-phenyl aldehyde as raw material, with with 1,1,1,3,3,3-hexamethyldisilazane (1.6g, 10mmol), just-and butyllithium (2.5M, 4mL, 10mmol), trimethylsilyl chloride (1.1g, 10mmol), and triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(2,3-two fluoro-6-aminomethyl phenyls)-3-front three for siloxy--2-azepine-1,3-butadiene, be orange glue, and under situation about not being further purified, be used for next step.
Embodiment 22c
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-aminomethyl phenyls) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00812
M.W.487.34 C 25H 18Cl 2F 2N 2O 2
With with the similar mode of method described in the embodiment 15c, the E/Z-6-chloro-3-that will in embodiment 15a, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g, 1.03mmol) with the 1-(2 that in embodiment 22b, prepares, 3-two fluoro-6-aminomethyl phenyls)-the 3-front three is for siloxy--2-azepine-1,3-divinyl (2.7g, 10.0mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (10mL) then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-aminomethyl phenyls) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (yield: 0.41g, 83.7%).
HRMS (ES +) m/z C 25H 18Cl 2F 2N 2O 2+ H[(M+H) +] calculated value: 487.0786 measured values: 487.0780.
Embodiment 22d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-aminomethyl phenyls) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00821
M.W.473.35 C 25H 20Cl 2F 2N 2O
With with the similar mode of method described in the embodiment 1d, racemize (2 ' the R that will in embodiment 22c, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-aminomethyl phenyls) spiral shell [3H-indoles-3,3 '-piperidines] and-2,6 ' (1H)-diketone (48.7mg, 0.1mmol) and NaBH 4(37.8mg, 1.00mmol) reaction in methyl alcohol (2mL) obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-aminomethyl phenyls) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white solid (yield 25.3mg, 53.5%).
HRMS (ES +) m/z C 25H 20Cl 2F 2N 2O+H[(M+H) +] calculated value: 473.0994.Measured value: 424.0992.
Embodiment 23a
Preparation intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-5-fluoro-1, the 3-dihydro-indol-2-one
Figure A200780008564D00822
M.W.308.14 C 15H 8Cl 2FNO
With with the similar mode of method described in the embodiment 1a, with 6-chloro-5-fluoro-1,3-dihydro-indol-2-one (0.25g, 1.35mmol) and 3-chloro-phenyl aldehyde (0.34g, 2.44mmol) and tetramethyleneimine (0.19g 2.68mmol) reacts in methyl alcohol, obtains E-and Z-6-chloro-3-(3-chloro-benzylidene)-5-fluoro-1, the mixture of 3-dihydro-indol-2-one is yellow solid.
According to the document program that does not have change: EP 153 818, preparation 6-chloro-5-fluoro-1,3-dihydro-indol-2-one.
Embodiment 23b
Preparation intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-5-fluoro-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester
Figure A200780008564D00831
M.W.408.26 C 20H 16Cl 2FNO 3
With with the similar mode of method described in the embodiment 15a, with E/Z-6-chloro-3-(3-chloro-benzylidene)-5-fluoro-1,3-dihydro-indol-2-one (0.45g, 1.46mmol) and tert-Butyl dicarbonate (0.4g, 1.83mmol) (Aldrich), triethylamine (0.5g, 4.95mmol) and 4-dimethylaminopyridine (5mg) in methylene dichloride (30mL), react, obtain E/Z-6-chloro-3-(3-chloro-benzylidene)-5-fluoro-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester, be yellow solid (yield: 0.6g, 100%).
Embodiment 23c
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00841
M.W.487.34 C 25H 18Cl 2F 2N 2O 2
With with the similar mode of method described in the embodiment 15b, the E/Z-6-chloro-3-that will in embodiment 23b, prepare (3-chloro-benzylidene)-5-fluoro-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g, 0.98mmol) with 1-(5-fluoro-2-aminomethyl phenyl)-3-front three of in embodiment 14a, preparing for siloxy--2-azepine-1,3-divinyl (2.1g, 8.37mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (10mL) then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (yield: 0.35g, 72.9%).
HRMS (ES +) m/z C 25H 18Cl 2F 2N 2O 2+ H[(M+H) +] calculated value: 487.0786.Measured value: 487.0779.
Embodiment 23d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
M.W.473.35 C 25H 20Cl 2F 2N 2O
With with the similar mode of method described in the embodiment 1d, racemize (2 ' the R that will in embodiment 23c, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2, (48.3mg is 0.1mmol) with excessive N aBH for 6 ' (1H)-diketone 4Reaction obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone in methyl alcohol (2mL), is white solid (yield 18.8mg, 39.9%).
HRMS (ES +) m/z C 25H 20Cl 2F 2N 2O+H[(M+H) +] calculated value: 473.0994.Measured value: 473.0992.
Embodiment 24a
Preparation intermediate 1-(1-ethyl-propenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure A200780008564D00851
M.W.211.38 C 11H 21NOSi
With with the similar mode of method described in the embodiment 1b, with 2-ethyl-but-2-ene aldehyde (1.54g, 10mmol) (TCI-US) replaces 3-chloro-phenyl aldehyde as raw material, with with 1,1,1,3,3, the 3-hexamethyldisilazane (1.6g, 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), and trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(1-ethyl-propenyl)-3-front three for siloxy--2-azepine-1, the 3-divinyl, and under situation about not being further purified, be used for next step.
Embodiment 24b
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00852
M.W.429.35 C 23H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 15c, the E/Z-6-chloro-3-that will in embodiment 15a, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g, 1.02mmol) with 1-(1-ethyl-propenyl)-3-front three of in embodiment 24a, preparing for siloxy--2-azepine-1,3-divinyl (2.1g, 9.93mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (20mL) then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (0.24g, 54.5%).
HRMS (ES +) m/z C 23H 22Cl 2N 2O 2+ H[(M+H) +] calculated value: 429.1131.Measured value: 429.1129.
Embodiment 24c
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00861
M.W.431.37 C 23H 24Cl 2N 2O 2
To the racemize that in embodiment 24b, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.3g, 0.70mmol) in the solution in ethyl acetate (30mL), add platinum oxide (0.35g, 1.54mmol).Under hydrogen (50psi), the suspension brute force that obtains is shaken 6h.Mixture is filtered by diatomaceous short pad.Filtrate is concentrated.With residuum by chromatogram (EtOAc:CH 2Cl 2=1:1) purifying obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone, is white solid (yield 0.11g, 37.7%).
HRMS (ES +) m/z C 23H 24Cl 2N 2O 2+ H[(M+H) +] calculated value: 431.1288 measured values: 431.1285.
Embodiment 24d
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00871
M.W.417.38 C 23H 26Cl 2N 2O
With with the similar mode of method described in the embodiment 1d, racemize (2 ' R, the 3R that will in embodiment 24d, prepare, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines] and-2,6 ' (1H)-diketone (73.6mg, 0.17mmol) and NaBH 4(64.3mg, 1.7mmol) reaction in methyl alcohol (3mL) obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (yield 10.5mg, 14.7%).
HRMS (ES +) m/z C 23H 26Cl 2N 2O+H[(M+H) +] calculated value: 417.1495.Measured value: 417.1494.
Embodiment 25a
Preparation intermediate 1-(2,5-dimethyl-phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure A200780008564D00872
M.W.247.42 C 14H 21NOSi
With with the similar mode of method described in the embodiment 1b, with 2,5-dimethyl-phenyl aldehyde (1.34g, 10mmol) (Aldrich) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1,1,3,3, the 3-hexamethyldisilazane (1.6g, 10mmol), n-Butyl Lithium (2.5M, 4mL, 10mmol), and trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(2,5-dimethyl-phenyl)-the 3-front three is for siloxy--2-azepine-1, the 3-divinyl is yellow glue, and is used for next step under situation about not being further purified.
Embodiment 25b
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl-phenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00881
M.W.465.38 C 26H 22Cl 2N 2O 2
With with the similar mode of method described in the embodiment 15c, the E/Z-6-chloro-3-that will in embodiment 15a, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g, 1.02mmol) with the 1-(2 that in embodiment 25a, prepares, 5-dimethyl-phenyl)-the 3-front three is for siloxy--2-azepine-1,3-divinyl (2.3g, 9.31mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (20mL) then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl-phenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid.
HRMS (ES +) m/z C 26H 22Cl 2N 2O 2+ H[(M+H) +] calculated value: 465.1131 measured values: 465.1128.
Embodiment 25c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(2,5-dimethyl-phenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00882
M.W.451.40 C 26H 24Cl 2N 2O
With with the similar mode of method described in the embodiment 1d, racemize (2 ' the R that will in embodiment 25b, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl-phenyl) spiral shell [3H-indoles-3,3 '-piperidines] (42.1mg is 0.09mmol) with excessive N aBH for-2,6 ' (1H)-diketone 4Reaction obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(2,5-dimethyl-phenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone in methyl alcohol (3mL), is white solid (yield 13.7mg, 33.8%).
HRMS (ES +) m/z C 26H 24Cl 2N 2O+H[(M+H) +] calculated value: 451.1339.Measured value: 451.1338.
Embodiment 26a
Preparation intermediate 1-(2,5-dimethyl-2H-pyrazole-3-yl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure A200780008564D00891
M.W.237.38 C 11H 19N 3OSi
With with the similar mode of method described in the embodiment 1b, with 2,5-dimethyl-2H-pyrazoles-3-formaldehyde (1.24g, 10mmol) (ASDI-INTER) replaces 3-chloro-phenyl aldehyde as raw material, with 1,1,1,3,3, the 3-hexamethyldisilazane (1.6g, 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), and trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(2,5-dimethyl-2H-pyrazole-3-yl)-the 3-front three is for siloxy--2-azepine-1, the 3-divinyl is yellow glue, and is used for next step under situation about not being further purified.
Embodiment 26b
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl-2H-pyrazole-3-yl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00901
M.W.455.35 C 23H 20Cl 2N 4O 2
With with the similar mode of method described in the embodiment 15c, the E/Z-6-chloro-3-that will in embodiment 15a, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g, 1.02mmol) with the 1-(2 that in embodiment 26a, prepares, 5-dimethyl-2H-pyrazole-3-yl)-the 3-front three is for siloxy--2-azepine-1,3-divinyl (2.5g, 10.5mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (15mL) then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl-2H-pyrazole-3-yl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (yield 0.14g, 30.4%).
HRMS (ES +) m/z C 23H 20Cl 2N 4O 2+ H[(M+H) +] calculated value: 455.1036 measured values: 455.1035.
Embodiment 26c
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl-2H-pyrazole-3-yl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00902
M.W.441.36 C 23H 22Cl 2N 4O
With with the similar mode of method described in the embodiment 1d, racemize (2 ' the R that will in embodiment 26b, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl-2H-pyrazole-3-yl) spiral shell [3H-indoles-3,3 '-piperidines] (81.6mg is 0.18mmol) with excessive N aBH for-2,6 ' (1H)-diketone 4Reaction obtains racemize (2 ' R, 3R in methyl alcohol (3mL), 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl-2H-pyrazole-3-yl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white amorphous substance (yield 42.9mg, 54.3%).
HRMS (ES +) m/z C 23H 22Cl 2N 4O+H[(M+H) +] calculated value: 441.1244.Measured value: 441.1244.
Embodiment 27
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-(morpholine-4-carbonyl)-2 '-(1-naphthyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
M.W.586.52 C 33H 29Cl 2N 3O 3
To the racemize that in embodiment 17c, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-naphthyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (30mg, 0.062mmol) in the solution in methylene dichloride (2mL), add morpholine-4-carbonyl chloride (13.9mg, 0.093mmol) solution in methylene dichloride and excess of triethylamine.With reaction mixture in stirring at room 2h, reflux 2h then.Reaction mixture is cooled off, and dilute with ethyl acetate.With the organic layer water, the salt water washing concentrates then.With residuum by chromatogram (EtOAc: the purifying of hexane=1:1), obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-(morpholine-4-carbonyl)-2 '-(1-naphthyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, it is recrystallization from the EtOAC-hexane, and needed product is provided, be white solid (yield 20.5mg, 56.9%).
MS (ES +) m/z C 33H 29Cl 2N 3O 3+ H[(M+H) +] calculated value: 586.1659.Measured value: 586.1657.
Embodiment 28a
Preparation intermediate E/Z-6-chloro-3-(4-chloro-benzylidene)-1, the 3-dihydro-indol-2-one
Figure A200780008564D00921
M.W.290.15 C 15H 9Cl 2NO
With with the similar mode of method described in the embodiment 1a, with 6-chlorine oxindole (2g, 11.4mmol) and 4-chloro-phenyl aldehyde (1.91g, 13.6mmol) (1.53g, 13.6mmol) (1.34mL 13.6mmol) reacts in methyl alcohol for (Aldrich) and piperidines, obtain E-and Z-6-chloro-3-(4-chloro-benzylidene)-1, the mixture of 3-dihydro-indol-2-one is yellow solid (yield: 3.3g, 100%).
Embodiment 28b
Preparation intermediate E/Z6-chloro-3-(4-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester
M.W.362.22 C 18H 13Cl 2NO 3
With with the similar mode of method described in the embodiment 4b, with E/Z-6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one (3.3g, 11.3mmol) with Vinyl chloroformate (1.62mL, 17.0mmol) and triethylamine (3.16mL 22.6mmol) reacts in methylene dichloride, obtain E/Z-6-chloro-3-(4-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester is yellow solid (yield 3.0g, 73%).
Embodiment 28c
Preparation intermediate racemize (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(4-chloro-phenyl-)-2 '-(3-fluorophenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester
Figure A200780008564D00931
M.W.527.38 C 27H 21Cl 2FN 2O 4
With with the similar mode of method described in the embodiment 4d, the E/Z-6-chloro-3-that will in embodiment 28b, prepare (4-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid, ethyl ester (0.4g, 1.1mmol) with 1-(3-fluorophenyl)-3-front three of in embodiment 5a, preparing for siloxy--2-azepine-1,3-divinyl (2.6g, 10.95mmol) in toluene, react, obtain racemize (2 ' S, 3S, 4 ' R)-and 6-chloro-4 '-(4-chloro-phenyl-)-2 '-(3-fluorophenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester (yield 0.45g, 77.6%).
Embodiment 28d
Preparation intermediate racemize (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(4-chloro-phenyl-)-2 '-(3-fluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D00932
M.W.455.314 C 24H 17Cl 2FN 2O 2
With with the similar mode of method described in the embodiment 4e, racemize (2 ' the S that will in embodiment 28c, prepare, 3S, 4 ' R)-6-chloro-4 '-(4-chloro-phenyl-)-2 '-(3-fluorophenyl)-2,3-dihydro-2, (0.45g is 0.85mmol) with NaOH (69.6mg for 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-carboxylic acid, ethyl ester, 1.71mmol) in methyl alcohol, react, obtain racemize (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(4-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white amorphous solid (yield 0.15g, 38.5%).
HRMS (ES +) m/z C 24H 17Cl 2FN 2O 2+ H[(M+H) +] calculated value: 455.0724 measured values: 455.0724.
Embodiment 28e
Preparation racemize (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(4-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00941
M.W.441.34 C 24H 19Cl 2FN 2O
With with the similar mode of method described in the embodiment 6c, racemize (2 ' the S that will in embodiment 28d, prepare, 3S, 4 ' R)-6-chloro-4 '-(4-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2, (150mg is 0.33mmol) with excessive NaBH for 6 ' (1H)-diketone 4Reaction obtains racemize (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(4-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone in methyl alcohol (3mL), is white solid (yield 75.9mg, 52.2%).
HRMS (ES +) m/z C 24H 19Cl 2FN 2O+H[(M+H) +] calculated value: 441.0931.Measured value: 441.0926.
Embodiment 29
Preparation racemize (2 ' S, 3S, 4 ' R)-1 '-tertiary butyl aminocarboxyl-6-chloro-4 '-(4-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00942
M.W.540.47 C 29H 28Cl 2FN 3O 2
To the racemize that in embodiment 28e, prepares (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(4-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (30mg, 0.068mmol) in the solution in methylene dichloride (10mL), isocyanato--2-methyl-propane (0.2mL) (Aldrich) to add 2-.With reaction mixture after stirred overnight at room temperature, remove and desolvate, obtain racemize (2 ' S, 3S, 4 ' R)-1 '-tertiary butyl aminocarboxyl-6-chloro-4 '-(4-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white powder (yield 37.1mg, 100%).
HRMS (ES +) m/z C 29H 28Cl 2FN 3O 2+ H[(M+H) +] calculated value: 540.1616.Measured value: 540.1606.
Embodiment 30
Preparation racemize (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(4-chloro-phenyl)-1 '-(3-cyano group-phenyl amino carbonyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00951
M.W.585.47 C 32H 23Cl 2FN 4O 2
To the racemize that in embodiment 28e, prepares (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(4-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (30mg, 0.068mmol) in the solution in methylene dichloride (10mL), add 3-isocyanato--benzonitrile (0.2mL) (Aldrich).With reaction mixture in stirred overnight at room temperature.Reaction mixture is diluted with methylene dichloride, and wash with water.With organic layer separation and concentrated.Residuum is suspended in the methylene dichloride (3mL), and filters, obtain white powder.Then filtrate is used chromatogram purification, obtain racemize (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(4-chloro-phenyl)-1 '-(3-cyano group-phenyl amino carbonyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white powder (yield 11.9mg, 29.9%).
HRMS (ES +) m/z C 32H 23Cl 2FN 4O 2+ H[(M+H) +] calculated value: 585.1255.Measured value: 585.1246.
Embodiment 31
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-1 '-(3-cyano group-phenyl amino carbonyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00961
M.W.585.47 C 32H 23Cl 2FN 4O 2
To the racemize that in embodiment 5d, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (30mg, 0.068mmol) in the solution in methylene dichloride (10mL), add 3-isocyanato--benzonitrile (12.7mg, 0.088mmol) (Aldrich) and ethyl-Diisopropylamine (0.1mL).With reaction mixture in stirred overnight at room temperature.Reaction mixture is diluted with methylene dichloride, and wash with water.With organic layer separation and concentrated.Residuum is suspended in the methylene dichloride (3mL), and filters, obtain white powder.Then filtrate is used chromatogram purification, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-1 '-(3-cyano group-phenyl amino carbonyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white powder (yield 16.8mg, 42.2%).
HRMS (ES +) m/z C 32H 23Cl 2FN 4O 2+ H[(M+H) +] calculated value: 585.1255.Measured value: 585.1255.
Embodiment 32
Preparation racemize (2 ' R, 3R, 4 ' S)-1 '-tertiary butyl aminocarboxyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00962
M.W.540.47 C 29H 28Cl 2FN 3O 2
With with the similar mode of method described in the embodiment 29, racemize (2 ' the R that will in embodiment 5d, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (30mg, 0.068mmol) and 2-isocyanato--2-methyl-propane (8.7mg, 0.088mmol) (Aldrich) in methylene dichloride, react, obtain racemize (2 ' R, 3R, 4 ' S)-1 '-tertiary butyl aminocarboxyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white solid (yield 37.1mg, 100%).
HRMS (ES +) m/z C 29H 28Cl 2FN 3O 2+ H[(M+H) +] calculated value: 540.1616.Measured value: 540.1608.
Embodiment 33
Preparation racemize (2 ' R, 3R, 4 ' S)-1 '-benzoyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00971
M.W.545.45 C 31H 23Cl 2FN 2O 2
To the racemize that in embodiment 5d, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (30mg, 0.068mmol) and the solution of excessive ethyl-Diisopropylamine in methylene dichloride (2.5mL) in, add 1 Benzoyl chloride (Aldrich).With reaction mixture in stirred overnight at room temperature.And then add two Benzoyl chlorides, and with reaction mixture in stirring at room 2h.Remove desolvate and with residuum with chromatogram (EtOAC: the purifying of hexane=1:1); obtain racemize (2 ' R; 3R; 4 ' S)-1 '-benzoyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2 (1H)-ketone; be white amorphous substance (yield 26.2mg, 70.6%).
HRMS (ES +) m/z C 31H 23Cl 2FN 2O 2+ H[(M+H) +] calculated value: 545.1194.Measured value: 545.1182.
Embodiment 34
Preparation racemize (2 ' R, 3R, 4 ' S)-1 '-ethanoyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
M.W.483.37 C 26H 21Cl 2FN 2O 2
To the racemize that in embodiment 5d, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (30mg, 0.068mmol) and the solution of excessive ethyl-di-isopropyl-amine in methylene dichloride (2.5mL) in, add 1 Acetyl Chloride 98Min..With reaction mixture in stirred overnight at room temperature.And then add two Acetyl Chloride 98Min.s, and with reaction mixture in stirring at room 2h.Remove desolvate and with residuum with chromatogram (EtOAC: the purifying of hexane=1:1); obtain racemize (2 ' R; 3R; 4 ' S)-1 '-ethanoyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2 (1H)-ketone; be white amorphous substance (yield 8.2mg, 25.0%).
HRMS (ES +) m/z C 26H 21Cl 2FN 2O 2+ H[(M+H) +] calculated value: 483.1037.Measured value: 483.1041.
Embodiment 35
Preparation racemize (2 ' R, 3R, 4 ' S)-1 '-[4-(amino carbonyl methyl)-piperazine-1-carbonyl]-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00982
M.W.610.52 C 31H 30Cl 2FN 5O 2
In 0 ℃, to the racemize that in embodiment 5d, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (30mg, 0.068mmol) and the solution of ethyl-di-isopropyl-amine (0.05mL) in methylene dichloride (2.5mL) in, add 10 phosgene (20%, in toluene).Reaction mixture is stirred 3h in 0 ℃.Then reaction mixture is warmed to room temperature, and adds 2-piperazine-1-base-ethanamide (27.9mg, 0.10mmol) (MatrixScientific).Behind stirring at room 2h, reaction mixture is concentrated.With residuum reversed-phase column purifying, obtain racemize (2 ' R, 3R, 4 ' S)-1 '-[4-(amino carbonyl methyl)-piperazine-1-carbonyl]-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white trifluoroacetate (yield 45.8mg, 93.1%).
HRMS (ES +) m/z C 31H 30Cl 2FN 5O 2+ H[(M+H) +] calculated value: 610.1783.Measured value: 610.1787.
Embodiment 36
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl)-1 '-[4-(3-methylsulfonyl-propyl group)-piperazine-1-carbonyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D00991
M.W.673.64 C 33H 35Cl 2FN 4O 4S
With with the similar mode of method described in the embodiment 35; racemize (2 ' the R that will in embodiment 5d, prepare; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2 (1H)-ketone (30mg; 0.068mmol) and 10 phosgene (20%; in toluene); ethyl-di-isopropyl-amine (0.05mL) and 1-(3-methylsulfonyl-propyl group)-piperazine (27.9mg; 0.1mmol) in methylene dichloride, react; obtain racemize (2 ' R; 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl)-1 '-[4-(3-methylsulfonyl-propyl group)-piperazine-1-carbonyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone; be the amorphous trifluoroacetate of white (yield: 22.3mg, 41.8%).
HRMS (ES +) m/z C 33H 35Cl 2FN 4O 4S+H[(M+H) +] calculated value: 673.1813 measured values: 673.1813.
Embodiment 37
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl)-1 '-[4-(2-oxo-2-tetramethyleneimine-1-base-ethyl)-piperazine-1-carbonyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
M.W.664.61 C 35H 36Cl 2FN 5O 3
With with the similar mode of method described in the embodiment 35, racemize (2 ' the R that will in embodiment 5d, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (30mg, 0.068mmol) and 10 phosgene (20%, in toluene), ethyl-di-isopropyl-amine (0.05mL) and 2-piperazine-1-base-1-tetramethyleneimine-1-base-ethyl ketone (19.7mg, 0.1mmol) (Aldrich) in methylene dichloride, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl)-1 '-[4-(2-oxo-2-tetramethyleneimine-1-base-ethyl)-piperazine-1-carbonyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be the amorphous trifluoroacetate of white (yield: 21.8mg, 39.4%).
HRMS (ES +) m/z C 35H 36Cl 2FN 5O 3+ H[(M+H) +] calculated value: 664.2252 measured values: 664.2249.
Embodiment 38
Preparation racemize (2 ' R, 3R, 4 ' S)-1 '-[4-(2-acetylamino-ethyl)-piperazine-1-carbonyl]-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
M.W.638.58 C 33H 34Cl 2FN 5O 3
With with the similar mode of method described in the embodiment 35; racemize (2 ' the R that will in embodiment 5d, prepare; 3R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3; 3 '-piperidines]-2 (1H)-ketone (30mg; 0.068mmol) and 10 phosgene (20%; in toluene); ethyl-di-isopropyl-amine (0.05mL) and N-(2-piperazine-1-base-ethyl)-ethanamide (24.9mg; 0.1mmol) in methylene dichloride, react; obtain racemize (2 ' R; 3R, 4 ' S)-1 '-[4-(2-acetylamino-ethyl)-piperazine-1-carbonyl]-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone; be the amorphous trifluoroacetate of white (yield: 23.3mg, 46.1%).
HRMS (ES +) m/z C 33H 34Cl 2FN 5O 3+ H[(M+H) +] calculated value: 638.2096 measured values: 638.2092.
Embodiment 39
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl)-1 '-[4-(2-hydroxyl-ethyl)-piperazine-1-carbonyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D01011
M.W.597.52 C 31H 31Cl 2FN 4O 3
With with the similar mode of method described in the embodiment 35, racemize (2 ' the R that will in embodiment 5d, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (30mg, 0.068mmol) and 10 phosgene (20%, in toluene), ethyl-di-isopropyl-amine (0.05mL) and 2-piperazine-1-base-ethanol (13.0mg, 0.1mmol) in methylene dichloride, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl)-1 '-[4-(2-hydroxyl-ethyl)-piperazine-1-carbonyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be the amorphous trifluoroacetate of white (yield: 25.2mg, 52.2%).
HRMS (ES +) m/z C 31H 31Cl 2FN 4O 3+ H[(M+H) +] calculated value: 597.1830 measured values: 597.1827.
Embodiment 40
Preparation racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-1 '-cyclohexyl aminocarboxyl-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D01021
M.W.566.51 C 31H 30Cl 2FN 3O 2
To the racemize that in embodiment 5d, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (30mg, 0.068mmol) solution in methylene dichloride (3mL), add isocyanato--hexanaphthene (11.0mg, 0.088mmol) (Aldrich).With reaction mixture in stirring at room 3h.Remove and to desolvate and residuum recrystallization from ethyl acetate/hexane, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-1 '-cyclohexyl aminocarboxyl-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be white amorphous solid (yield 22.7mg, 57.7%).
HRMS (ES +) m/z C 31H 30Cl 2FN 3O 2+ H[(M+H) +] calculated value: 566.1112.Measured value: 566.1773.
Embodiment 41
Preparation racemize (2 ' R, 3R, 4 ' S)-1 '-benzylamino carbonyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D01022
M.W.574.49 C 32H 26Cl 2FN 3O 2
With with the similar mode of method described in the embodiment 40, racemize (2 ' the R that will in embodiment 5d, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (25mg, 0.057mmol) and isocyanatomethyl-benzene (11.7mg, 0.088mmol) in methylene dichloride, react, obtain racemize (2 ' R, 3R, 4 ' S)-1 '-benzylamino carbonyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (yield: 11.5mg, 35.3%).
HRMS (ES +) m/z C 32H 26Cl 2FN 3O 2+ H[(M+H) +] calculated value: 574.1459 measured values: 574.1452.
Embodiment 42a
Preparation intermediate 1,2-two fluoro-4-isopropoxy-benzene
Figure A200780008564D01031
M.W.172.18 C 9H 10F 2O
To 3, ((54g is 38.4mmol) with 2-iodo-propane to add salt of wormwood for 5g, the 38.4mmol) solution in acetone (50mL) for 4-two fluoro-phenol.With reaction mixture reflux 24h.With rough thing cooling, and by diatomaceous short pad filtration.Filtrate concentrated and with residuum by chromatogram (EtOAc: the purifying of hexane=1:9), obtain 1,2-two fluoro-4-isopropoxy-benzene are colorless oil (yield 6.12g, 92.3%).
Embodiment 42b
Preparation intermediate 2,3-two fluoro-6-isopropoxy-phenyl aldehydes
Figure A200780008564D01032
M.W.200.19 C 10H 10F 2O 2
With with the similar mode of method described in the embodiment 22a, will in embodiment 42a, prepare 1,2-two fluoro-4-isopropoxy-benzene (5.77g, 33.5mmol) and lithium diisopropylamine (20.5mL, 1.8M is in THF, 36.9mmol), N, N-dimethyl-methane amide (3.11mL, 40.2mmol) reaction, and be used in acetate (8.0g, 134mmol) quencher in the tetrahydrofuran (THF), obtain 2,3-two fluoro-6-isopropoxy-phenyl aldehydes are white crystal (yield: 6.02g, 89.9%).
Embodiment 42c
Preparation intermediate 1-(2,3-two fluoro-6-isopropoxy-phenyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure A200780008564D01041
M.W.313.42 C 15H 21F 2NO 2Si
With with the similar mode of method described in the embodiment 1b, will in embodiment 42b, prepare 2,3-two fluoro-6-isopropoxy-phenyl aldehyde (2.0g, 10mmol) replace 3-chloro-phenyl aldehyde, with 1,1 as raw material, 1,3,3, the 3-hexamethyldisilazane (1.6g, 10mmol), just-butyllithium (2.5M, 4mL, 10mmol), and trimethylsilyl chloride (1.1g, 10mmol), triethylamine (1.4g, 13mmol) and Acetyl Chloride 98Min. (1.0g, 13mmol) reaction, obtain 1-(2,3-two fluoro-6-isopropoxy-phenyl)-the 3-front three is for siloxy--2-azepine-1, the 3-divinyl is yellow oil, and is used for next step under situation about not being further purified.
Embodiment 42d
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
M.W.531.39 C 27H 22Cl 2F 2N 2O 3
With with the similar mode of method described in the embodiment 15c, the E/Z-6-chloro-3-that will in embodiment 15a, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (0.4g, 1.02mmol) with the 1-(2 that in embodiment 42c, prepares, 3-two fluoro-6-isopropoxy-phenyl)-the 3-front three is for siloxy--2-azepine-1,3-divinyl (2.5g, 7.98mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (10mL) then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (0.41g, 75.9%).
HRMS (ES +) m/z C 27H 22Cl 2F 2N 2O 3+ H[(M+H) +] calculated value: 531.1049.Measured value: 531.1049.
Embodiment 42e
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D01051
M.W.547.46 C 27H 22Cl 2F 2N 2O 2S
With with the similar mode of method described in the embodiment 37, racemize (2 ' the R that will in embodiment 42d, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (0.45g, 0.85mmol) with 2,4-pair-(4-p-methoxy-phenyl)-1,3-dithia-2,4-two phosphetane 2, (0.6g 1.8mmol) reacts in toluene the 4-disulfide, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (yield 0.36g, 78.3%).
HRMS (ES +) m/z C 27H 22Cl 2F 2N 2O 2S+H[(M+H) +] calculated value: 547.0820.Measured value: 547.0821.
Embodiment 42f
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's ethyl ester
Figure A200780008564D01061
M.W.617.48 C 30H 28Cl 2F 2N 4O 4
With with the similar mode of method described in the embodiment 20b, racemize (2 ' the R that will in embodiment 42d, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (0.30g, 0.55mmol) and the carbazic acid ethyl ester (0.3g, 2.97mmol), mercuric acetate (0.30g, 0.95mmol) and triethylamine (0.1g, 0.99mmol) reaction in tetrahydrofuran (THF) (40mL), obtain racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's ethyl ester, be white solid (yield 0.25g, 73.5%).
HRMS (ES +) m/z C 30H 28Cl 2F 2N 4O 4+ H[(M+H) +] calculated value: 617.1529.Measured value: 617.1523.
Embodiment 42g
Preparation racemize (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(2,3-two fluoro-6-isopropoxy-phenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone
Figure A200780008564D01062
M.W.571.41 C 28H 22Cl 2F 2N 4O 3
With with the similar mode of method described in the embodiment 20c, racemize (2 ' the R that will in embodiment 42f, prepare, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-isopropoxy-phenyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's ethyl ester (0.21g, 0.34mmol) heating in toluene (20mL), obtain racemize (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(2,3-two fluoro-6-isopropoxy-phenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone, be white solid (yield 0.13g, 68.4%).
HRMS (ES +) m/z C 28H 22Cl 2F 2N 4O 3+ H[(M+H) +] calculated value: 571.1110.Measured value: 571.1107.
Embodiment 42h
Preparation chirality (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(2,3-two fluoro-6-isopropoxy-phenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone
Figure A200780008564D01071
M.W.571.41 C 28H 22Cl 2F 2N 4O 3
By the racemize (5 ' R of chirality SFC among embodiment 42g, preparing, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(2,3-two fluoro-6-isopropoxy-phenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)] carry out the separation of two kinds of enantiomers in-2 (1H)-ketone (30mg), so that chirality (5 ' R to be provided, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(2,3-two fluoro-6-isopropoxy-phenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone, for white solid (12mg, 40%) (RO5167429-000) and chirality (5 ' S, 3S, 7 ' R)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(2,3-two fluoro-6-isopropoxy-phenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone, for white solid (5mg, 17%) (RO5167428-000).
Embodiment 43a
Preparation intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(2-trimethylsilyl-ethoxyl methyl)-1, the 3-dihydro-indol-2-one
M.W.420.41 C 21H 23Cl 2NO 2Si
In 0 ℃, to the E/Z-6-chloro-3-that in embodiment 4a, prepares (3-chloro-benzylidene)-1,3-dihydro-indol-2-one (2.3g, 7.9mmol) at N, in the solution in N-dimethyl-methane amide (20mL), add NaH (60%, in mineral oil) (0.32g, 7.9mmol) (Aldrich), then drip 2-(trimethylsilyl) ethoxyl methyl chlorine in tetrahydrofuran (THF) (20mL) (1.32g, 7.9mmol).Reaction mixture in 0 ℃ of stirring 0.5h, is poured in ice-water then.With twice of ethyl acetate extraction of rough thing.With the organic layer Na that merges 2SO 4Dry.Remove desolvate and with residuum by chromatogram (EtOAc: the purifying of hexane=1:5), obtain E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(2-trimethylsilyl-ethoxyl methyl)-1, the 3-dihydro-indol-2-one is yellow oil (yield 3.0g, 90%).
Embodiment 43b
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure A200780008564D01091
M.W.585.58 C 30H 31Cl 2FN 2O 3Si
With with the similar mode of method described in the embodiment 4d, the E/Z-6-chloro-3-that will in embodiment 43a, prepare (3-chloro-benzylidene)-1-(2-trimethylsilyl-ethoxyl methyl)-1,3-dihydro-indol-2-one (1.0g, 2.38mmol) with 1-(3-fluoro-phenyl)-3-front three of in embodiment 15a, preparing for siloxy--2-azepine-1, the 3-divinyl reacts in toluene (60mL), obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl)-2,3-dihydro-2,6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane, be oily matter (yield 1.06g, 75%).
Embodiment 43c
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
Figure A200780008564D01092
M.W.571.60 C 30H 33Cl 2FN 2O 2Si
With with the similar mode of method described in the embodiment 1d, racemize (2 ' the R that will in embodiment 43b, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl)-2,3-dihydro-2, (0.50g is 0.85mmol) with excessive NaBH for 6 '-dioxo spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane 4Reaction obtains racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (yield 78.0mg, 16.0%) in methyl alcohol (40mL).
Embodiment 43d
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-1 '-[(tertbutyloxycarbonyl) methyl]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluoro-phenyl) spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane
M.W.685.75 C 36H 43Cl 2FN 2O 4Si
In room temperature, to the racemize that in embodiment 43c, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(72mg is 0.126mmol) at N for (3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane, in the solution in N-dimethyl-methane amide (10mL), add the bromo-tert.-butyl acetate (0.08g, 0.41mmol) and cesium carbonate (0.3g, 0.92mmol).Reaction mixture is stirred 2h under nitrogen, pour into saturated NH then 4In the Cl aqueous solution.With the mixture ethyl acetate extraction.Organic layer is merged, use Na 2SO 4Dry and concentrated.With residuum by chromatogram purification, obtain racemize (2 ' R, 3R, 4 ' S)-1 '-[(tertbutyloxycarbonyl) methyl]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluoro-phenyl) spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (yield 64.0mg, 74.1%).
Embodiment 43e
Preparation racemize (2 ' R, 3R, 4 ' S)-1 '-hydroxycarbonyl group methyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D01111
M.W.499.37 C 26H 21Cl 2FN 2O 3
To the racemize that in embodiment 43d, prepares (2 ' R, 3R, 4 ' S)-1 '-[(tertbutyloxycarbonyl) methyl]-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluoro-phenyl) spiral shell [indoles-3,3 '-piperidines]-1-methoxy ethyl trimethyl silane (50mg, 0.073mmol) solution in methylene dichloride (0.5mL), add trifluoroacetic acid (0.5mL).With reaction mixture in stirring at room 2h.Reaction mixture is diluted with ethyl acetate, and use saturated sodium bicarbonate, water, the salt water washing, and concentrate.Residuum is dissolved in the methyl alcohol (0.5mL), and uses N, N '-diisopropylethylamine (0.5mL) handles, and backflow 2h.Reaction mixture is diluted with methylene dichloride, and wash with 4N NaOH.Water layer is separated, and, use ethyl acetate extraction then with the acidifying of 6N HCl solution.Organic layer is merged, dry and concentrated, obtain racemize (2 ' R, 3R, 4 ' S)-1 '-carboxyl methyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (yield 22.5mg, 61.8%).
HRMS (ES +) m/z C 26H 21Cl 2FN 2O 3+ H[(M+H) +] calculated value: 499.0986 measured values: 499.0982
Embodiment 44a
Preparation intermediate 4-methyl-2-methylene radical-penta-1-alcohol
Figure A200780008564D01112
M.W.114.19 C 7H 14O
In 0 ℃, (14g, 0.25mol) (40g 0.25mol) in (Aldrich) solution in ether, drips isopropylmagnesium chloride (2M, 375mL, 0.75mol) solution in tetrahydrofuran (THF) for (Aldrich) and CuI to propargyl alcohol.With reaction mixture in stirring at room 48h.With the saturated NH of reaction mixture 4Twice of extracted with diethyl ether used in the quencher of the Cl aqueous solution.Organic layer is merged, water, MgSO is used in the salt water washing 4Drying is filtered and is concentrated.With residuum by chromatogram (EtOAc: the purifying of hexane=1:8), obtain 4-methyl-2-methylene radical-penta-1-alcohol, for colorless oil (yield, 27g, 95%) similarly changes by Duboudin, J.G.; Jousseaume, B. are reported in J.OrganometallicChem. (1979), and 168 (1), 1-11 and J.Organometallic Chem. (1975), 91 (1), among the C1-C3.
Embodiment 44b
Preparation intermediate 4-methyl-2-methylene radical-valeral
Figure A200780008564D01121
M.W.112.17 C 7H 12O
In-78 ℃, (32.5g 255mmol) in (Aldrich) solution in methylene dichloride (200mL), is added dropwise to methyl-sulphoxide (36.mL, 510mmol) solution in methylene dichloride (40mL) to oxalyl chloride.Behind 5min, drip the 4-methyl-2-methylene radical-penta-1-alcohol (26.5g, 230mmol) solution in methylene dichloride (10mL) that in embodiment 44a, prepare.Reaction mixture is stirred 15min in-78 ℃.(110mL 950mmol), and is warmed to room temperature with reaction mixture and at leisure in stirring at room 45min to add triethylamine.Add entry, and organic layer is separated.With the water layer extracted with diethyl ether.Organic layer is merged, use 10%HCl, saturated NaHCO 3, MgSO is used in the salt water washing 4Drying, and concentrate, obtain rough 4-methyl-2-methylene radical-valeral, be yellow oil (yield 21g, 77%).
Embodiment 44c
Preparation intermediate 1-(3-methyl isophthalic acid-methylene radical-butyl)-3-front three is for siloxy--2-azepine-1,3-butadiene
Figure A200780008564D01122
M.W.225.41 C 12H 23NOSi
With with the similar mode of method described in the embodiment 1b, (11g 100mmol) replaces 3-chloro-phenyl aldehyde as raw material to the 4-methyl-2-methylene radical-valeral that will prepare in embodiment 44b, with with 1,1,1,3,3, the 3-hexamethyldisilazane (16g, 100mmol), just-butyllithium (2.5M, 40mL, 100mmol), and trimethylsilyl chloride (11g, 100mmol), triethylamine (13.6g, 14mmol) and Acetyl Chloride 98Min. (10.2g, 14mmol) reaction, obtain 1-(3-methyl isophthalic acid-methylene radical-butyl)-3-front three for siloxy--2-azepine-1, the 3-divinyl, and under situation about not being further purified, be used for next step.
Embodiment 44d
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-methyl isophthalic acid-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone
Figure A200780008564D01131
M.W.443.38 C 24H 24Cl 2N 2O 2
With with the similar mode of method described in the embodiment 15b, the E/Z-6-chloro-3-that will in embodiment 15a, prepare (3-chloro-benzylidene)-2-oxo-2,3-dihydro-indoles-1-carboxylic acid tert-butyl ester (2g, 5mmol) with 1-(3-methyl isophthalic acid-methylene radical-butyl)-3-front three of in embodiment 44c, preparing for siloxy--2-azepine-1,3-divinyl (21g, 93mmol) in toluene, react, react in methylene dichloride with trifluoroacetic acid (20mL) then, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-methyl isophthalic acid-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone is white solid (1.3g, 59%).
HRMS (ES +) m/z C 24H 24Cl 2N 2O 2+ H[(M+H) +] calculated value: 443.1288.Measured value: 443.1285
Embodiment 44e
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D01141
M.W.459.44 C 24H 24Cl 2N 2OS
With with the similar mode of method described in the embodiment 2c, racemize (2 ' the R that will in embodiment 44d, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl) spiral shell [3H-indoles-3,3 '-piperidines]-2,6 ' (1H)-diketone (1.4g, 3.1mmol) with 2,4-pair-(4-p-methoxy-phenyl)-1,3-dithia-2,4-two phosphetane2,4-disulfide (1.7g, 4.25mmol) in toluene, react, obtain racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be pale solid (yield 1.2g, 84%).
HRMS (ES +) m/z C 24H 24Cl 2N 2OS+H[(M+H) +] calculated value: 459.1059.Measured value: 459.1055.
Embodiment 44f
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-6-subunit] hydrazine carboxylic acid's tert-butyl ester
Figure A200780008564D01142
M.W.557.53 C 29H 34Cl 2N 4O 3
With with the similar mode of method described in the embodiment 20b, racemize (2 ' the R that will in embodiment 44e, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (0.7g, 1.5mmol) and tert-butyl carbazate (1.4g, 11mmol), mercuric acetate (0.5g, 1.6mmol) reaction in tetrahydrofuran (THF) (50mL), obtain racemize (2 ' R, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-the 6-subunit] hydrazine carboxylic acid's tert-butyl ester, be pale solid (yield 0.8g, 96%).
Embodiment 44g
Preparation intermediate racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-) 6 '-hydrazono--2 '-(1-methylene radical-butyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone
Figure A200780008564D01151
M.W.457.41 C 24H 26Cl 2N 4O
Trifluoroacetic acid (10mL) is joined the racemize (2 ' R that in embodiment 44f, prepares, 3R, 4 ' S)-[6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-methylene radical-butyl)-2,3-dihydro-2-oxo-spiral shell [3H-indoles-3,3 '-piperidines]-the 6-subunit] hydrazine carboxylic acid's tert-butyl ester (0.6g, 1.1mmol) solution in methylene dichloride (20mL).With mixture in stirring at room 1h.Evaporating solvent.In this residuum, add saturated NaHCO 3Solution, and use ethyl acetate extraction.Organic layer is merged, and MgSO is used in water and salt water washing 4And dried overnight obtains rough racemize (2 ' R, 3R in a vacuum, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-6 '-hydrazono--2 '-(1-methylene radical-butyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone, be yellow glue (yield: 0.5g, 100%).
Embodiment 44h
Preparation racemize (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(1-methylene radical-butyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone
M.W.467.40 C 25H 24Cl 2N 4O
Racemize (2 ' the R that will in embodiment 44g, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-6 '-hydrazono--2 '-(1-methylene radical-butyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (0.2g, 0.43mmol) at formic acid (20mL, 85%, Aldrich) middle backflow 1.5h.Reaction mixture is cooled to room temperature, concentrates.In residuum, add saturated NaHCO 3Solution, and with ethyl acetate-methyl alcohol (9; 1) extracting twice.Organic layer is merged, and MgSO is used in water and salt water washing 4Drying, and by column chromatography (EtOAc:MeOH=10; 1) purifying obtains the racemize (5 ' R, the 3R that need, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(1-methylene radical-butyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone, be white solid (yield 0.15g, 75%).
HRMS (ES +) m/z C 25H 24Cl 2N 4O+H[(M+H) +] calculated value: 467.1400.Measured value: 467.1397.
Embodiment 44i
Preparation chirality (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(1-methylene radical-butyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone
Figure A200780008564D01161
M.W.467.40 C 25H 24Cl 2N 4O
By chirality SFC, from racemize (5 ' R, the 3R that among embodiment 44h, prepares, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(1-methylene radical-butyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)] carry out the separation of two kinds of enantiomers in-2 (1H)-ketone (85mg), so that chirality (5 ' R to be provided, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(1-methylene radical-butyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone are white solid (31mg, 37%) (RO5170646-000) and chirality (5 ' S, 3S, 7 ' R)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(1-methylene radical-butyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone, be white solid (30mg, 35%).
Embodiment 45
Preparation racemize (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-3 '-methyl-5 '-(1-methylene radical-butyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone
Figure A200780008564D01171
M.W.481.43 C 26H 26Cl 2N 4O
With with the similar mode of method described in the embodiment 44i, racemize (2 ' the R that will in embodiment 44h, prepare, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-6 '-hydrazono--2 '-(1-methylene radical-butyl)-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (0.16g, 0.35mmol) backflow 3h in Glacial acetic acid (10mL), obtain racemize (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-3 '-methyl-5 '-(1-methylene radical-butyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone, be white solid (yield 29mg, 17%).
HRMS (ES +) m/z C 26H 26Cl 2N 4O+H[(M+H) +] calculated value: 481.1557.Measured value: 481.1554.
Embodiment 46
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-(1, the 4-piperazinyl)-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone
M.W.390.87 C 23H 17ClN 2O 2
To the racemize that in embodiment 21a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (48.1mg, 0.1mmol) in the stirred solution in THF (3mL), add HgCl 2(Aldrich, 100mg) and piperazine (Aldrich, 25mg 0.30mmol), and reflux mixture heating up and spend the night.Mixture is cooled to room temperature and filtration.Filtrate is concentrated, and residuum is composed purifying (30min in the enterprising circumstances in which people get things ready for a trip of ISCO machine.5%2M ammonia in methyl alcohol/EtOAc), obtain pale solid (yield, 24mg, 45%).
MS?m/z(M+H) +：537
Embodiment 47
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-[4-[1,1-dimethyl oxyethyl group-carbonyl] amino] ethylamino-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone
Figure A200780008564D01181
M.W.611.55 C 32H 33Cl 2FN 4O 2
To the racemize that in embodiment 21a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (96.2mg, 0.2mmol) in the stirred solution in THF (6mL), add HgCl 2(Aldrich, 82mg, 0.3mmol) and (2-amino-ethyl)-t-butyl carbamate (Aldrich, 48mg 0.30mmol), and reflux mixture heating up and spend the night.Mixture is cooled to room temperature and filtration.Filtrate is concentrated, and residuum is composed purifying (30min in the enterprising circumstances in which people get things ready for a trip of ISCO machine.5% methyl alcohol/EtOAc), obtain pale solid.52mg，50％。
MS?m/z(M+H) +：611
Embodiment 48
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-[4-amino] ethylamino-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone, trifluoroacetic acid
Figure A200780008564D01191
M.W.511.43 C 27H 25Cl 2FN 4O
Racemize (2 ' the R that will in embodiment 47, prepare, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-[4-[1,1-dimethyl oxyethyl group-carbonyl] amino] ethylamino-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-(40mg 0.074mmol) is dissolved in the 30%TFA/CH of 1.5ml to 2-ketone 2Cl 2In, and with mixture in stirring at room 30 minutes.Decompression removes down and desolvates, and with the residuum freeze-drying, obtains pale solid.44mg。
MS?m/z(M+H) +：511
Embodiment 49
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-(4-methyl isophthalic acid-piperazinyl)-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone
M.W.551.50 C 30H 29Cl 2FN 4O
To the racemize that in embodiment 21a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (48.4mg, 0.1mmol) in the stirred solution in THF (3mL), add HgCl 2(Aldrich, 82mg, 0.3mmol) and N-methyl-piperazine (Aldrich, 29.4mg 0.30mmol), and reflux mixture heating up and spend the night.Mixture is cooled to room temperature and filtration.Filtrate is concentrated, and residuum is composed purifying (30min in the enterprising circumstances in which people get things ready for a trip of ISCO machine.5%2M ammonia in methyl alcohol/EtOAc), obtain pale solid.22mg，40％。
MS?m/z(M+H) +：551
Embodiment 50a
Preparation intermediate 1,1-dioxo-tetrahydrochysene-thiapyran-4-ketone
Figure A200780008564D01201
M.W.148.18 C 5H 8O 3S
To tetrahydric thiapyran-4-ketone (Aldrich, 5.30g, 43.1mmol) in the stirred solution in the EtOAc of 50mL, with the speed of avoiding refluxing drip 32% peracetic acid (24g, 110mmol).After adding, mixture is cooled to room temperature, and filters because of body, obtain white solid, 5.69g, 89%.
Embodiment 50b
Preparation intermediate 4-(1,1-dioxo-six hydrogen-thiapyran-4-yl)-piperazine-1-carboxylic acid tert-butyl ester
Figure A200780008564D01202
M.W.318.44 C 14H 26N 2O 4S
Under the help of some heating, (6g 40.5mmol) is dissolved in the 1.2-ethylene dichloride (250ml) with tetrahydrochysene-4H-thiapyran-4-ketone.When temperature turns back to room temperature, add the 1-Boc-piperazine (Aldrich, 7.62g, 41mmol), sodium triacetoxy borohydride (Aldrich, 17.01,56.7mmol), then add Glacial acetic acid (2.4g, 41mmol).With reaction mixture in stirred overnight at room temperature.To react the water quencher, and mixture will be distributed.Organic layer is separated, and water layer is extracted with 1.2-ethylene dichloride (3x20mL).Extract is incorporated into organic moiety, and with solution Na 2SO 4Drying is filtered and is concentrated, and obtains white solid.White solid is being used under 30 minutes the situation of 2-7%MeOH/EtOAc wash-out, and purifying on the ISCO machine obtains white solid.Yield, 9.3g, 69%.MS?m/z(M+H) +：319
Embodiment 50c
Preparation intermediate 1-(1,1-dioxo-six hydrogen-thiapyran-4-yl)-piperazine
Figure A200780008564D01211
M.W.218.32 C 9H 18N 2O 2S
To 4-(1,1-dioxo-six hydrogen-thiapyran-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (8.02g, 25mmol) in the stirred solution in 45 ℃ methyl alcohol (150mL), be added in 4NHCl in the 1.4-diox (100mmol, 25mL).Mixture in 45 ℃ of stirring 7h, is indicated complete reaction up to TLC (5% methyl alcohol in EtOAc).Decompression removes down and desolvates, and obtains white solid.7.24g，99.5％。
MS?m/z(M+H) +：218
Embodiment 50d
Preparation racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-[[tetrahydrochysene-1,1-dioxo-2H-thiapyran-4-yl] piperazinyl-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone
Figure A200780008564D01212
M.W.669.65 C 34H 35Cl 2FN 4O 3S
To the racemize that in embodiment 21a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (48.4mg, 0.1mmol) in the stirred solution in THF (4mL), add HgCl 2(Aldrich, 105mg, 0.38mmol) and 1-(1,1-dioxo-six hydrogen-thiapyran-4-yl)-piperazine (embodiment 243c, 44mg, 0.15mmol) and triethylamine (45mg 0.45mmol), and refluxes mixture heating up and spends the night.Mixture is cooled to room temperature and filtration.Filtrate is concentrated, and residuum is composed purifying (30min in the enterprising circumstances in which people get things ready for a trip of ISCO machine.5% methyl alcohol/EtOAc), obtain pale solid.21mg，40％。
MS?m/z(M+H) +：669
Embodiment 51
Preparation racemize (2 ' R; 3 ' R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-[4-(3-methyl sulphonyl)-propyl group] piperazinyl-spiral shell [3H-indoles-3; 3 '-2 '; 3 '; 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone
Figure A200780008564D01221
M.W.657.64 C 33H 35Cl 2FN 4O 3S
To the racemize that in embodiment 21a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (48.4mg, 0.1mmol) in the stirred solution in THF (4mL), add HgCl 2(Aldrich, 91mg, 0.33mmol) and 1-(3-methylsulfonyl-propyl group)-piperazine (US23289,36.4mg, 0.15mmol) and triethylamine (31mg 0.30mmol), and refluxes mixture heating up and spends the night.Mixture is cooled to room temperature and filtration.Filtrate is concentrated, and residuum is composed purifying (30min in the enterprising circumstances in which people get things ready for a trip of ISCO machine.5% methyl alcohol/EtOAc), obtain pale solid.14mg，21％。
MS?m/z(M+H) +：657
Embodiment 52
Preparation racemize (2 ' R; 3 ' R; 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-[1-methyl sulphonyl-4-piperidyl] amino-spiral shell [3H-indoles-3; 3 '-2 '; 3 '; 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone
Figure A200780008564D01231
M.W.629.59 C 31H 31Cl 2FN 4O 3S
To the racemize that in embodiment 21a, prepares (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl)-6 '-sulfo-spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone (48.4mg, 0.1mmol) in the stirred solution in THF (4mL), add HgCl 2(Aldrich, 35mg, 0.12mmol) and 1-methylsulfonyl-piperidin-4-yl amine (WO 2003/097048,87.6mg, 0.15mmol) and triethylamine (41mg 0.40mmol), and spends the night mixture heating up backflow.Mixture is cooled to room temperature and filtration.Filtrate is concentrated, and residuum is composed purifying (30min, 5% methyl alcohol/EtOAc), obtain pale solid in the enterprising circumstances in which people get things ready for a trip of ISCO machine.8mg，13％。
MS?m/z(M+H) +：630
Embodiment 53
Activity test in vitro
Test by HTRF (homogeneous phase time discrimination fluorescence), measure compound and suppress interactional ability between p53 and the MDM2 albumen, in HTRF (homogeneous phase time discrimination fluorescence) test, the MDM2 of reorganization GST-mark is attached on the peptide, and described peptide is similar to the MDM2-interaction area (Lane etc.) of p53.The combination of GST-MDM2 albumen and p53-peptide (at biotinylation on its N-end) is by writing down at anti--GST antibody of europium (Eu)-mark and the FRET (fluorescence resonance energy transmission) between chain enzyme antibiotin-bonded allophycocyanin (APC).
At cubic capacity is 40uL; accommodate: 90nM biotinylation peptide; 160ng/mlGST-MDM2; 20nM chain enzyme antibiotin-APC (PerkinElmerWallac); anti--GST-the antibody (PerkinElmerWallac) of 2nM Eu-mark; 0.2% bovine serum albumin(BSA) (BSA); in the flat 384-orifice plate of black (Costar) of 1mM dithiothreitol (DTT) (DTT) and 20mM Tris-borate salt solution (TBS) damping fluid, the following test: the GST-MDM2 (640ng/ml working solution) of 10uL in reaction buffer joined in each hole.The compound (diluting with 1:5 in reaction buffer) of 10uL dilution is joined in each hole, mix by vibration.The biotinylation p53 peptide (180nM working solution) of 20uL in reaction buffer joined in each hole, and on vibrator, mix.In 37 ℃ of incubation 1h.Adding chain enzyme antibiotin-APC and the Eu-of 20uL in containing the TBS damping fluid of 0.2%BSA resists-GST mixtures of antibodies (6nMEu-resists-GST and 60nM chain enzyme antibiotin-APC working solution), in room temperature vibration 30 minutes, and use can TRF plate reader in 665 and 615nm (Victor 5, PerkinElmerWallac) reading.If do not specify, reagent is available from Sigma Chemical Co..
Show bioactive IC of the present invention 50Show the activity that is lower than about 10 μ M.
Some representational numerical value are as follows:
Embodiment number IC 50 (μ M) 0.2%BSA
8c 5.2123
11c 6.9498
16c 2.3103
44h 1.0308

Claims (19)

1. compound that is selected from following formula I, formula II and formula III:
Figure A200780008564C00021
With
Figure A200780008564C00022
Wherein
X is selected from hydrogen, halogen, and cyano group, nitro, ethynyl, cyclopropyl, methyl, ethyl, sec.-propyl, methoxyl group, and vinyl,
Y is hydrogen or fluorine,
R 4, R 5Be selected from hydrogen and low alkyl group,
R 1And R 8In one be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle of replacement, cycloalkyl, the cycloalkyl that replaces, cycloalkenyl group and the cycloalkenyl group that replaces, and another is a hydrogen
R 6And R 7In one be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl that replaces, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle that replaces, cycloalkyl, the cycloalkyl of replacement, cycloalkenyl group and the cycloalkenyl group that replaces, and another is a hydrogen, low alkyl group or cyano group
R 2Be selected from hydrogen, low alkyl group, the low alkyl group of replacement, C (=O) R 9, C (=O) NHR 9, C (=O) NR 9R 9' and C (=O) OR 9,
R 3Be selected from NHR 9, SR 9, and NR 9R 9 ',
R 9Be selected from low alkyl group, the low alkyl group of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle of replacement, the cycloalkyl of cycloalkyl and replacement,
R 9Be selected from the low alkyl group of low alkyl group and replacement,
And at R 9And R 9 'Situation under, they can connect independently with formation and are selected from ring texture in the heterocycle of heterocycle or replacement, and
R 10Be selected from hydrogen, hydroxyl and low alkyl group,
And pharmaceutical salts and ester.
2. the compound of a following formula I V:
Wherein
X is Cl or Br,
Y is a hydrogen,
R 1Be hydrogen,
R 4And R 5All be hydrogen,
R 6Be hydrogen,
R 7Be to be selected from the phenyl of the replacement in the following groups or the heteroaryl of replacement:
Figure A200780008564C00032
R 8Be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, cycloalkyl, the cycloalkyl of replacement, the cycloalkenyl group of cycloalkenyl group and replacement,
R 3Be selected from NHR 9And NR 9R 9 ',
R 9Be selected from low alkyl group, the low alkyl group of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle of replacement, the cycloalkyl of cycloalkyl and replacement,
R 9Be selected from the low alkyl group of low alkyl group and replacement,
And at R 9And R 9 'Situation under, they can connect independently with formation and are selected from ring texture in the heterocycle of heterocycle or replacement,
And pharmaceutical salts and ester.
3. the compound of a following formula V:
Figure A200780008564C00041
Wherein
X is Cl or Br,
Y is a hydrogen,
R 1Be hydrogen,
R 4And R 5All be hydrogen,
R 6Be hydrogen,
R 7Be to be selected from the phenyl of the replacement in the following groups or the heteroaryl of replacement:
Figure A200780008564C00042
R 8Be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, cycloalkyl, the cycloalkyl of replacement, the cycloalkenyl group of cycloalkenyl group and replacement,
R 10Be selected from hydrogen, hydroxyl, and methyl,
And pharmaceutical salts and ester.
4. the compound of a following formula VI:
Figure A200780008564C00051
Wherein
X is Cl or Br,
Y is a hydrogen,
R 1Be hydrogen,
R 4And R 5All be hydrogen,
R 6Be hydrogen,
R 7Be to be selected from the phenyl of the replacement in the following groups or the heteroaryl of replacement:
Figure A200780008564C00052
R 8Be selected from low alkyl group, the alkyl of replacement, low-grade alkenyl, the low-grade alkenyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, cycloalkyl, the cycloalkyl of replacement, the cycloalkenyl group of cycloalkenyl group and replacement,
R 2Be selected from hydrogen, low alkyl group, replacement
Low alkyl group, C (=O) R9, C (=O) NHR 9, C (=O) NR 9R 9 'And C (=O) OR 9,
R 9Be selected from low alkyl group, the low alkyl group of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the cycloalkyl of cycloalkyl and replacement,
R 9Be selected from the low alkyl group of low alkyl group and replacement,
And at R 9And R 9 'Situation under, they can connect independently with formation and are selected from ring texture in the heterocycle of heterocycle and replacement,
And pharmaceutical salts and ester.
5. the compound of a following formula VII:
Figure A200780008564C00061
Wherein
X is Cl or Br,
Y is a hydrogen,
R 1Be hydrogen,
R 4And R 5All be hydrogen,
R 6Be hydrogen,
R 8Be the phenyl that replaces, it is selected from:
And
R 7Be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle of replacement, cycloalkyl, the cycloalkyl of replacement, the cycloalkenyl group of cycloalkenyl group and replacement,
R 2Be selected from hydrogen, low alkyl group, the low alkyl group of replacement, C (=O) R 9, C (=O) NHR 9, C (=O) NR 9R 9 'And C (=O) OR 9,
R 9Be selected from low alkyl group, the low alkyl group of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the cycloalkyl of cycloalkyl and replacement,
R 9 'Be selected from the low alkyl group of low alkyl group and replacement,
And at R 9And R 9 'Situation under, they can connect independently with formation and are selected from ring texture in the heterocycle of heterocycle and replacement,
And pharmaceutical salts and ester.
6. the compound of claim 1, it is selected from:
Racemize (2 ' S, 3S, 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-(2, the 2-dimethyl propyl) spiral shells [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' S, 3R)-6-chloro-2 '-(3-chloro-phenyl-)-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-4 '-sec.-propyl-6 '-(methylthio group) spiral shell [3H-indoles-3,3 '-pyridine]-2 (1H)-ketone,
Racemize (2 ' S, 3S, 4 ' S)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-ethyl spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-fluorophenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-2 '-(3-chloro-phenyl-)-4 '-phenyl spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S, 5 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5 '-methyl-2 '-(2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-cyano-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone and
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2, the 3-3,5-dimethylphenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone.
7. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[2-(trifluoromethyl)-phenyl)] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' S, 3R)-6-chloro-4 '-(3-chloro-phenyl-)-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-6 '-(methylthio group)-2 '-[2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-pyridine]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-[5-fluoro-2-(trifluoromethyl)-phenyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,4 difluorobenzene base) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-p-methoxy-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-naphthyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3-pyridyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(3,4-two fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone and
Racemize (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(3, the 4-difluorophenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone.
8. the compound of claim 1, it is selected from:
Racemize (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(5-fluoro-2-aminomethyl phenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,3-two fluoro-6-aminomethyl phenyls) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-5-fluoro-2 '-(5-fluoro-2-aminomethyl phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(1-ethyl-propyl group) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(2,5-dimethyl-phenyl) spiral shells [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(2,5-dimethyl-2H-pyrazole-3-yl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-1 '-(morpholine-4-carbonyl)-2 '-(1-naphthyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(4-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' S, 3S, 4 ' R)-1 '-tertiary butyl aminocarboxyl-6-chloro-4 '-(4-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone and
Racemize (2 ' S, 3S, 4 ' R)-6-chloro-4 '-(4-chloro-phenyl)-1 '-(3-cyano group-phenyl amino carbonyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone.
9. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-1 '-(3-cyano group-phenyl amino carbonyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-tertiary butyl aminocarboxyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-benzoyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-ethanoyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-[4-(amino carbonyl methyl)-piperazine-1-carbonyl]-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl)-1 '-[4-(3-methylsulfonyl-propyl group)-piperazine-1-carbonyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl)-1 '-[4-(2-oxo-2-tetramethyleneimine-1-base-ethyl)-piperazine-1-carbonyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-[4-(2-acetylamino-ethyl)-piperazine-1-carbonyl]-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone and
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl)-1 '-[4-(2-hydroxyl-ethyl)-piperazine-1-carbonyl] spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone.
10. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl)-1 '-cyclohexyl aminocarboxyl-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-benzylamino carbonyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(2,3-two fluoro-6-isopropoxy-phenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone,
Chirality (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(2,3-two fluoro-6-isopropoxy-phenyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-3 '-hydroxyl spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone,
Racemize (2 ' R, 3R, 4 ' S)-1 '-hydroxycarbonyl group methyl-6-chloro-4 '-(3-chloro-phenyl)-2 '-(3-fluoro-phenyl) spiral shell [3H-indoles-3,3 '-piperidines]-2 (1H)-ketone,
Racemize (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(1-methylene radical-butyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone,
Chirality (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-5 '-(1-methylene radical-butyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone,
Racemize (5 ' R, 3R, 7 ' S)-6-chloro-7 '-(3-chloro-phenyl-)-3 '-methyl-5 '-(1-methylene radical-butyl)-5 ', 6 ', 7 ', 8 '-tetrahydrochysene-spiral shell [3H-indoles-3,6 '-(1,2,4-triazolo [4,3-a] pyridine)]-2 (1H)-ketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-(1, the 4-piperazinyl)-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone and
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-[4-[1,1-dimethyl oxyethyl group-carbonyl] amino] ethylamino-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone.
11. the compound of claim 1, it is selected from:
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-[4-amino] ethylamino-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone, trifluoroacetic acid,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-(4-methyl isophthalic acid-piperazinyl)-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone,
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-[[tetrahydrochysene-1,1-dioxo-2H-thiapyran-4-yl] piperazinyl-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-[4-(3-methyl sulphonyl)-propyl group] piperazinyl-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone and
Racemize (2 ' R, 3 ' R, 4 ' S)-6-chloro-4 '-(3-chloro-phenyl-)-2 '-(5-fluoro-2-methyl-phenyl)-6 '-[1-methyl sulphonyl-4-piperidyl] amino-spiral shell [3H-indoles-3,3 '-2 ', 3 ', 4 ', 5 '-tetrahydrochysene-pyridine]-2-ketone.
12. a pharmaceutical preparation, it comprises the compound of following formula I, formula II or formula III:
Figure A200780008564C00111
Or
Figure A200780008564C00112
Wherein
X is selected from hydrogen, halogen, and cyano group, nitro, ethynyl, cyclopropyl, methyl, ethyl, sec.-propyl, methoxyl group, and vinyl,
Y is hydrogen or fluorine,
R 4, R 5Be selected from hydrogen and low alkyl group,
R 1And R 8In one be selected from low alkyl group,
The low alkyl group that replaces, low-grade alkenyl, the low-grade alkenyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle of replacement, cycloalkyl, the cycloalkyl of replacement, cycloalkenyl group and the cycloalkenyl group that replaces, and another is hydrogen,
R 6And R 7In one be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl that replaces, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle that replaces, cycloalkyl, the cycloalkyl of replacement, cycloalkenyl group and the cycloalkenyl group that replaces, and another is a hydrogen, low alkyl group or cyano group
R 2Be selected from hydrogen, low alkyl group, the low alkyl group of replacement, C (=O) R 9, C (=O) NHR 9, C (=O) NR 9R 9 'And C (=O) OR 9,
R 3Be selected from NHR 9, SR 9, and NR 9R 9 ',
R 9Be selected from low alkyl group, the low alkyl group of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle of replacement, the cycloalkyl of cycloalkyl and replacement,
R 9 'Be selected from the low alkyl group of low alkyl group and replacement,
And at R 9And R 9 'Situation under, they can connect independently with formation and are selected from ring texture in the heterocycle of heterocycle or replacement,
R 10Be selected from hydrogen, hydroxyl and low alkyl group,
And pharmaceutical salts and ester, and pharmaceutical carrier or vehicle.
13. according to the pharmaceutical preparation of claim 12, it is used for the treatment of cancer, particularly solid tumor, mammary gland, colon, lung and tumor of prostate more specifically.
14. compound according to claim 1 to 11 as medicine.
15. be used for the treatment of cancer, particularly solid tumor, the compound according to claim 1 to 11 of mammary gland, colon, lung and tumor of prostate more specifically.
16. the compound according to claim 1 to 11 is used for the treatment of cancer in preparation, particularly solid tumor, the application in the medicine of mammary gland, colon, lung and tumor of prostate more specifically.
17. a method for preparing the compound of following formula VIII or formula VIII ',
Figure A200780008564C00121
Or
Figure A200780008564C00122
Wherein
X is selected from hydrogen, halogen, cyano group, nitro, cyclopropyl, methyl, ethyl, and sec.-propyl;
Y is hydrogen or fluorine;
R 1Be hydrogen;
R 4And R 5Be hydrogen or low alkyl group;
R 8Be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle of replacement, cycloalkyl, the cycloalkyl of replacement, cycloalkenyl group and the cycloalkenyl group that replaces;
R 6And R 7In one be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl that replaces, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle that replaces, cycloalkyl, the cycloalkyl of replacement, cycloalkenyl group and the cycloalkenyl group that replaces, and another is a hydrogen, cyano group or low alkyl group
This method comprises: at about 110-160 ℃ and under anhydrous condition, make the compound of following formula,
Figure A200780008564C00131
With the compound reaction of following formula,
Figure A200780008564C00132
Compound with preparation formula V or V '.
18. a method for preparing the compound of following formula VIII or VIII ',
Figure A200780008564C00133
Or
Figure A200780008564C00134
Wherein
X is selected from hydrogen, halogen, cyano group, nitro, cyclopropyl, methyl, ethyl, and sec.-propyl;
Y is hydrogen or fluorine;
R 1Be hydrogen;
R 4And R 5Be hydrogen or low alkyl group;
R 8Be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl of replacement, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle of replacement, cycloalkyl, the cycloalkyl of replacement, cycloalkenyl group and the cycloalkenyl group that replaces;
R 6And R 7In one be selected from low alkyl group, the low alkyl group of replacement, low-grade alkenyl, the low-grade alkenyl that replaces, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, the heterocycle that replaces, cycloalkyl, the cycloalkyl of replacement, cycloalkenyl group and the cycloalkenyl group that replaces, and another is a hydrogen, cyano group or low alkyl group
This method comprises: the compound that makes following formula
Figure A200780008564C00141
With suitable blocking group (Pg) reaction, so that the compound of following formula to be provided,
Figure A200780008564C00142
Then, at about 110-160 ℃ and under anhydrous condition, the reaction of the compound of itself and following formula,
Figure A200780008564C00143
Then with the product deprotection that obtains, with the compound of preparation formula V and V '.
19. aforesaid basically new compound, intermediate, methods and applications.
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